Nitin Purandare Peninsula College of Medicine and Dentistry Devon Partnership Mental Health Trust

1. Role of vascular diseases and cerebral emboli in causation and progression of Alzheimer’s disease and vascular dementia Nitin Purandare Peninsula College of Medicine and Dentistry Devon Partnership Mental Health Trust

2. Outline • Epidemiology • Vascular diseases and causation of dementia • Role of cerebral emboli • Vascular diseases and progression of dementia

3. Epidemiology • 24.3 million people worldwide • 81.1 million affected by 2040 • 821,884 people with dementia in the UK • the annual cost of care = £23 billion • 21 million people in UK know close friend of family member with dementia • 1 in 3 people over 65 will have dementia by the time they die • About 50% remain undiagnosed

4. Dementia Registers(Connolly et al 2011) • 351 general practices in six Primary Care Trusts • The observed prevalence of dementia amongst patients 65 years and over was 3% [range 2.8 to 3.2]. • For an average size general practice (list size of 5269 patients) approximately 27 [95CI 22, 32] patients with dementia may remain undiagnosed.

5. Dementia: types and overlap DLB 15-20% VaD 20-30% AD 50-60% FTD/ Alcohol etc 5-10%

6. Nun study • 102 college educated nuns aged 76-100 years • Clinical and neuropathological assessment of dementia and Alzheimer’s disease • 61 met neuropathological criteria for AD • Fewer neuropathologic lesions of AD required for the clinical manifestation of dementia in those who had infarcts in basal ganglia, thalamus or deep white matter Snowdon et al, JAMA, 1997

7. Mixed AD and VaD • 156 brains of AD patients • Braak NFT, Aβ deposition, cortical microinfarcts (CMI) and thalamic and basal ganglia lacunes (TBGL) predicted 27% of CDR variability and 49% of presence of dementia • Classification of dementia • NFT > II and CMI + TBGL > 2  mixed dementia • NFT ≤ II and CMI + TBGL > 2  pure VaD • NFT > II and CMI + TBGL ≤ 2  pure AD Gold et al, Brain, 2007

8. Role of vascular diseasesin causation of dementia • Epidemiological evidence • Evidence from RCTs

9. Honolulu Asia Aging Study(White and Launer, 2006) • HHP 1965 n = 8006 HAAS 1991 n = 3731 Follow ups  5 over 14 years Autopsy 2006 n = 650 • Hypertension in midlife is a risk factor for dementia in late life • Systolic BP >= 160 HR for dementia 4.8 (2.0-11.0) • HT  Brain wt; SP count, hippo atrophy • SP + lacunar infarcts risk of clinical dementia (Launer et al, ‘00; Petrovitch et al, ’00; Korf et al, ’04; Petrovitch et al, 2005)

10. Kungsholmen project Age ≥ 75 yrs and no dementia (n=947) Two follow ups approx 3 years apart 186 dementia at FU1 118 dementia at FU2 643 no dementia Results No drop in BP prior to 3 years before diagnosis of dementia BP markedly decreased over 3 years before dementia diagnosis and afterwards If baseline SBP<160, drop of ≥15 mm Hg at FU1 associated with increased risk of dementia at FU2 (RR 3.1) - dose effect in subjects with vascular disease? Decline in BP over time and risk of dementia • Mechanism • Risk Factor: Drop in BP  cerebral hypoperfusion  neurodegeneration  clinical dementia • Risk Marker: Neurodegeneration in strategic areas  drop in BP  cerebral hypoperfusion  clinical dementia Qiu et al, Stroke, 2004

11. 2,356 members of health maintenance organisation aged ≥ 65 yrs Average follow up 8 yrs 380 (16%) incident dementia Risk of dementia 65-74 yrs group High SBP and borderline-high DBP ≥ 75 yrs group Trend towards high SBP being associated with low dementia risk  The association between BP and dementia depends on age at which BP is measured and not the time relative to the onset of dementia Effect of age on the relationship between blood pressure and risk of dementia Li et al, Journal of American Geriatric Society, 2007

12. Syst-Eur trial (Forette et al, 1998 & 2002) • Inclusion • 60+ • Systolic BP 160-219 and Diastolic BP < 95 mm of HG • Intervention • Nitrendipine + enalapril + hydrochlorothiazide (n=1238) • Placebo (n=1180) • 2 yr FU  incidence of dementia reduced by 50% • Extended FU over 3.9 years (controls given anti-HT) • Incident dementia 32  64 (41 AD) • Long term Rx reduced incident dementia by 55% (from 7.4 to 3.3 cases per 1000 patient years) • Rx of 1000 patients for 5 years can prevent 20 cases of dementia

14. Cholesterol and risk of AD • Raised cholesterol in midlife is a risk factor for dementia (most cohort studies) • Decreasing cholesterol in late-life is risk marker (Mielke et al, 2005; Solomon et al, 2009) • Cohort studies on statins and other LLA • Mixed results • Statins > LLA? • Simavastatin associated with reduced risk (Wolozin et al, BMC Medicine, 2007) • RCTs • No effect  HPS collaborative study, PROSPER • +ve effect?  ADCLT (Sparks et al, Arch Neurol, 2005) • CLASP, LEADE, ESPRIT, PIT-ROAD • Chole, 24SOHC, 27OHC and BBB • Low cholesterol in cell membranes in AD Blood Brain Chol Chol 24SOHC 27OHC BBB

15. Multiple risk factors and WMH • Midlife raised systolic BP + midlife raised cholesterol + APOE4  increased risk of dementia (Kivipelto et al, 2002) • Metabolic syndrome  risk factor in those with high inflammation (Yaffe K, 2007)  only in those with MCI (Solfrizzi et al. 2011) • VRF increase risk of AD in those with MCI and those treated appear to have reduced conversion (Li et al, 2011) • Subcortical WMH increase risk of AD in those with MCI (Prasad et al, 2011)  Only non-AD dementia (Staekenborg et al 2009) • Metaanlyses  HR 1.9 (1.3, 2.8) (Debette & Markus, 2010) • Calculating risk of dementia in an individual • Mitnitski et al, European J of Neurology, 2006 • Kivipelto et al, Lancet Neurol, 2006

16. Predicting dementia risk • Population based CAIDE study • 1409 people seen in midlife and 20 years later • 61 (4%) developed dementia • Predictors • High age • low education • Hypertension • Hypercholesterolaemia • obesity Kivipelto et al, Lancet Neurology, 2006

17. RCT evidence • General population or with a specific risk factor • Hypertension No (Staessen et al, 2010) • Statins  NO (HPS 2002, Shepherd et al 2002) • Folic acid  small, positive effect on cognition (Durga et al 2007) • Cognitive training  no effect (Owen et al 2010) • Memory problems: “at risk” of dementia • NSAID, Cox-2 inhibitors  NO (Martin et al 2008; Meinert et al 2009) • Statins  NO? (ADCLT; Sparks et al 2005) • Vitamin E  NO (Petersen et al 2005) • Cholinesterase inhibitors  NO (Petersen et al 2005 + others) • Physical activity  small positive effect on cognition (van Uffelen et al 2007; Lautenschlager et al 2008)

18. Potential impact of delaying onset of dementia: Australian perspective  Will decrease prevalence of dementia in 2050 by 44%  Will decrease prevalence of dementia in 2050 by 6% Jorm et al, Australian & New Zealand Journal of Psychiatry, 2005

19. Questions for future research? • Therapeutic time window between midlife and late life? • Precise mechanism of any protective agent? • Is ‘lower the better’ doctrine about BP true for preventing and slowing progression of dementia? • How to account for the interaction and additive effects of multiple risk factors? • Who should be the target patients? • Better understanding of mechanisms involved in vascular brain damage?

20. Spontaneous cerebral emboli (SCE) Emboli cause stroke Micro-emboli may be asymptomatic but are common in severe/ symptomatic carotid disease predict future risk of strokes in at risk patients Sources of SCE Carotid arteries & aorta Heart (valvular disease and AF) Venous emboli (paradoxical embolisation)

21. Research questions Could asymptomatic spontaneous cerebral emboli cause progressive brain damage or dementia? Could some of such emboli originate via paradoxical embolisation through a patent foramen ovale?

22. Wellcome Trust • Cross-sectional, case-control study • to investigate spontaneous cerebral emboli and paradoxical embolisation through venous to arterial circulation shunt (v-aCS) in Alzheimer’s disease and vascular dementia 85 Alzheimer’s disease (AD) 85 vascular dementia (VaD) 85 controls for AD 85 controls for VaD 150 controls recruited (20 duplicated for the main analyses)

23. Consensus criteria: CCNICHS, 1995 “Embolic signals should be transient (lasting <300 milliseconds), at least 3 dB higher than the background blood flow signal, unidirectional, within the Doppler spectrum, and accompanied by an audible snap, chirp, or moan” Detection of one or more embolic signals was defined as “SCE positive”

24. Recruitment

26. Spontaneous cerebral emboli in dementia Purandare et al, BMJ, 2006 * Adjusted for cardiovascular risk factors

29. SCE are more frequent in dementia but are they associated with any of the behavioural and psychological symptoms of dementia?

30. Late onset depression • age of onset after the age of 60 years • a lower family load for depressive disorder • fewer pre-morbid personality disturbances • more vascular risk factors • white matter hyperintensities on neuroimaging • concomitant cognitive deficits • resistance to initial antidepressant monotherapy • less likely to show cognitive-affective symptoms, including dysphoria, worthlessness/guilt and suicidal ideation Alexoupolus, 2005; Fiske et al., 2009; Alexopoulos, 2005; Baldwin, 2005; Brodaty et al., 2001; Krishnan et al., 1995; Zisook et al., 2007

31. SCE are more frequent in dementia but are they associated with the ‘clinically relevant depressive symptom’ (NPI-D) in dementia?

32. Emboli are associated with depressive symptoms in dementia Purandare et al, 2006, BJP * p < 0.05

33. SCE are more frequent in dementia andare associated with depressive symptoms but does the SCE positive status predict a more rapid progression of dementia?

34. 80 AD + 80 VaD Wellcome Trust 150 Controls Alzheimer’s Society 39 new 118 old Total 157 Six monthly assessments for two years (n = 157) SCE and progression of dementia 6 mth = 132 SCE positive patients showed a more rapid cognitive and functional decline

35. Emboli status predicts progression of dementia over 6 months Purandare et al, Biol Psychiatry, 2007 * corrected for age, gender, type of dementia, cardiovascular risk factors, and other baseline characteristics associated with the change score over time (p<0.15).

36. 85 AD + 85 VaD Wellcome Trust 150 Controls Alzheimer’s Society 39 new 118 old Total 157 Six monthly assessments for two years (n = 157) SCE and Progression of dementia 6 mth = 132 SCE positive patients showed a more rapid cognitive and functional decline 12 mth = 129 18 mth = 96 24 mth = 91 SCE positive patients show a more severe cognitive and functional decline

37. Cerebral emboli and progression of dementia over two years (AJP, 2012) 144 patients with dementia (84 AD, 60 VaD) SCE were detected (SCE+ve) in 63 (44%) dementia patients, 36 (43%) in AD and 27 (45%) in VaD patients. ADAS-Cog score increased by a mean of 13.8 (95% CI: 9.1, 18.5) in SCE+ve and by 6.7 (2.8, 10.5) in SCE-ve patients (p=0.007). IDDD scores increased by 57.8 (39.4, 76.2) in SCE +ve patients compared with 20.2 (8.7, 31.8) for the SCE –ve patients (p=0.068). NPI scores increased in SCE+ve patients by 12.7 (6.7, 18.6) compared with -3.8 (-7.3, -0.3) in SCE-ve patients (p<0.001).

38. SCE are associated with depressive symptoms and predict a more rapid cognitive and functional decline in dementiabut do SCE show similar associations in controls without dementia?

39. 85 AD + 85 VaD Wellcome Trust 150 Controls Alzheimer’s Society 39 new 118 old • After 2 years from baseline: • Cognitive function • Depression Total 157 Six monthly assessments for two years (n = 157) SCE and Progression of dementia 96 controls followed 6 mth = 132 SCE positive patients showed a more rapid cognitive and functional decline 12 mth = 129 18 mth = 96 24 mth = 91 SCE positive patients show a more severe cognitive and functional decline

40. Baseline emboli status and cognition at after 2 years in controls (OudeVoshaar et al, 2007, IJGP) @ predictors of cognitive decline – age, carotid artery disease, h/o stroke  Non-participants had more severe cardiovascular risk factors and included 48% (10/21) of the SCE positive controls

41. Baseline emboli status predicts depressive symptoms at 2 year follow-up in older controls (OudeVoshaar et al, AJGP, 2007) * SCE were independent predictors of MADRS after correction for age, gender, baseline cognitive status, and cardiovascular risk factors

42. 85 AD + 85 VaD Wellcome Trust 150 Controls Alzheimer’s Society 39 new 118 old • After 2 years from baseline: • Cognitive function • Depression Total 157 Six monthly assessments for two years (n = 157) SCE and Progression of dementia 96 controls followed 6 mth = 132 SCE positive patients showed a more rapid cognitive and functional decline • SCE positive controls showed more depressive symptoms, but not cognitive decline • 48% drop out of SCE positive controls? • Depression > Dementia? • Depression  Dementia? 12 mth = 129 18 mth = 96 24 mth = 91 SCE positive patients show a more rapid progression over two years Aetiology & mechanism?

43. Asymptomatic spontaneous cerebral emboli are frequent in patients with Alzheimer’s disease and vascular dementia and are associated with clinically relevant depressive symptoms and a more rapid progression of clinical dementia over two years compared to those who do not have emboli.

44. Role of vascular diseases in progression of dementia • Evidence • Current clinical practice

45. Progression of dementia • Control of high blood pressure, atrial fibrillation and angina may slow cognitive decline in dementia (Mielke et al, 2007) • Not all studies find comorbid vascular diseases to predict a more rapid progression of dementia (Regan et al, 2006) • HT and hypercholesterolaemia not associated with progression in AD and diabetes  slower decline (Musicco et al, 2009) • In AD and stroke or myocardial infarction the rate of progression is affected by apolipoprotein E4 status (Mielke et al, 2011) • EVA study  Vascular care in patients with AD with cerebrovascular lesions  slower progression of WMLs (Richard et al, 2010)

46. Predicting mortality in memory clinic • 1138 consecutive memory clinic patients • Mean FU 2.6 years • WMH and microbleeds  HR 1.2 • Mortality especially high in those with microbleeds and global cortical atrophy Henneman et al, 2009

47. Participating Primary Care Trusts Ashton, Leigh & Wigan Bolton Bury Manchester Oldham Stockport

48. Comorbidity in dementia(BJGP 2012)

49. PriDem – dementia care • 80% (599/745) patients had an annual dementia review, but just 51% (305/599) had social care review, and 61% (367/599) discussion of carers included in this. • Despite high prevalence of vascular disease, 26% (262/994) were currently prescribed antipsychotics; 57% (148/262) of these had record of medication reviewed in the previous 6 months, and 77% (203/262) in the previous 15 months. • Patients with AD and practices run by more than one GP were associated with better quality of care overall.

50. PriDem - vascular care • Care was (significantly) poorer for PWD compared to those without dementia on 22/30(73%) indicators. • Peripheral pulses check, neuropathy testing, retinal screening, and BMI monitoring for diabetes; cholesterol records for Stroke and CHD patients; and smoking cessation advice received the lowest provision of care. • After multivariate adjustment, better quality of vascular care was found for males, those living in the community rather than care homes, and those with more comorbid physical conditions and medications.