1. Knut Engedal, Professor of Geriatric Psychiatry. Norwegian Centre of Ageing and Health Oslo University Hospital, Ullevaal, Oslo, Norway Depression in AD and other dementias

2. Significant BPSD in demented NH patients (NPI) % Selbaek, Kirkevold, Engedal. Int J Geriatr Psychiatry, 2007; 23(9): 843-9

3. Major and Minor depression in AD referred to specialist practices MajorMinor Ballard et al, 1996 (n=124)25 %27.4 % Lyketsos et al, 1997 (n=109)22 %27 % Starkstein et al, 2005 (n=670)26 %26 % Early onset cases Rosness et al, 2009 (n=221)10 %56 % (submitted)

4. Depression – 1 year follow-up of 546 NH patients (Cornell 7+) 12 months YesNo BaselineYes 52 (9.5/44.8%) Persistence 64 (11.7 %)116 (21,2 %) Prevalence at baseline No 64 (11,7 %) Incidence 382430 116 (21.2 %) Prevalence at 12 months 430546 Barca, Engedal, Laks, Selbaek. J Affective Disorders, 2009, Epub

5. Incidence and persistency of depression in AD Incidence 6 -12 months6-18 % Persistency 6-12 months30-50% L yketsos CG and Olin J. Biol Psychiatry 2002; 52: 243-52

6. Consequences of depression in AD Greater impairment in quality of life ( Gonzales-Salvador et al, 2002) Greater impairment in ADL (Lyketsos et al, 1997, Starkstein et al, 2005, Lenze et al. 2005 and several more studies) Earlier entry into residential care (Steele et al 1990) Increase in mortality, especially in early phase of dementia (Hoch et al, 1993; Engedal 1996, Suh et al, 2004, Barca et al, 2009) Greater burden on carers (Gonzales- Salvador, 2002, Rosness, 2009)

7. Why high persistence rate and poor prognosis? Due to treatment factors Not treated Treated with drugs with too low dosages? Drugs not effective? Due to our conception of depression in AD? Diagnostic criteria Typical symptoms Heterogeneity Psychological or biological factors Similarities and interaction between depression and AD

8. Cochrane Database Seven studies were included: Fuchs 1993, Lyketsos 2003, Nyth 1992, Petracca 1996, Petracca 2001, Reifler 1989 and Roth 1996. Results and conclusions: Weak evidence for effect. Significant fewer patients with side-effects in the placebo group. Lack of large scale good studies Bains J et al. Issue 4, 2002

9. Why high persistence rate and poor prognosis? Due to treatments Not treated Treated with drugs with too low dosages? Drugs not effective? Due to our conception of depression in AD? Typical symptoms Heterogeneity Psychological or biological factors Similarities and interaction between depression and AD

10. Depression in AD D ifferent from that seen in non-demented subjects More common ? (motivational) overlap with AD symptoms? Less common ? (mood symptoms) Lack of motivation Anhedonia Anxiety Irritability Agitation Delusions Hallucinations Depressed mood Guilt Hopelessness Suicidal behaviour Rosenberg and Lyketsos

11. Depressive symptoms in AD patients compared to depressed non demented patients – Different? AD patients with depression (n=92) did not differ from depressed patients (n=47) without dementia Chemerinski et al,. Am J Psychiatry 2001; 158: 68-72

12. Depression in dementia ( n=902 ) –Cornell scale symptoms depressed mood less common? % Depressive symptoms by severity of dementia Barca, Selbaek, Laks and Engedal, Int J Geriatr Psychiatry 2008; 23(10): 1058-65

13. Major vs minor depression in dementia RDC_ Major RDC_ Minordepression Loss of interest100 %50 % Anxiety93.5 %61.8 % Depressed mood90.3 %100 % Irritability90.6 %64.7 % Lack of mood reactivity74.2 %47.1 % Agitation71 %50.0 % Retardation61.3 %29.4 % Lack of energy45.2 %26.5 % Ballard et al. J Affective Disorders 1996

14. ‘Sad mood’ in Major and Minor depression by AD severity Major depressionMinor depression n=177n=177 Mild dementia91%75% Moderate dementia90%76% Severe dementia94%44% Starkstein et al, 2005; 162: 2086-93

15. Why high persistence rate and poor prognosis? Due to treatments Not treated Treated with drugs with too low dosages? Drugs not effective? Due to our conception of depression in AD? Typical symptoms Heterogeneity Various risk factors Psychological or biological factors Similarities and interaction between depression and AD

16. Risk factors of depression in AD  Depression earlier in life  18%(Agbayewa et al, JAGS 1986; 34: 561-84.  30% (Rovner et al, AJGP 1989; 146: 350-39)  26% in EO (Rosness et al, IJGP 2009)  Family history of depression (first degree)  Poor physical health  Female gender  Marital Status  ADL impairment/Dependency?

17. Cornell score by CDR and physical health Mean Cornell sum in 902 patients in NH of whom 80 % have dementia Physical Health CDR GoodFairly GoodPoor/Very Poor No dementia2.33.15.7 Mild dementia3.54.15.9 Moderate dementia2.74.56.1 Severe dementia3.86.37.7 Barca, Selbaek, Laks, Engedal. Int J Geriatr Psychiatry, 2009, 4:

18. Aetiology of depression in AD -mechanisms Psychological explanation? High prevalence of depression in mild stage of dementia due to insight of functional loss (ADL impairments, word finding problems, social stress) Biological explanation? High prevalence of depression in severe stage of dementia due to structural damages Both?, than a bi-modal distribution

19. Severity of AD and depression - A systematic review Associations between severity of AD and depressive symptoms 19 studies No association Associations between severity of AD and a depressive disorder 7 studies No association Verkaik, R. Int J Geriatr Psychiatry, 2007; 222: 1063-86

20. mildmoderatesevere

21. Depressive symptoms by dementia severity Mean scores of Cornell sub scales (factor analysis) by CDR group, n=902 ScoresCDR<1CDR 1CDR 2CDR 3P value 1 Cornell Sum3.874.845.216.69<0.001 Mood1.531.831.661.980.326 Physical0.480.680.691.33<0.001 Cyclic0.45 0.640.79<0.001 Retardation0.330.380.360.88<0.001 Behavioural0.570.730.931.40<0.001 Barca, Selbaek, Laks, Engedal, Int J Geriatr Psychiatry 2008 ; 23: 1058-65

22. Aetiology of depression in AD -mechanisms Psychological explanation? High prevalence of depression in mild stage of dementia due to insight of functional loss (ADL impairments, word finding problems, social stress) Biological explanation? High prevalence of depression in severe stage of dementia due to structural damages Selective loss of noradrenergic neurons in loecus cerulus Selective loss of dopamiergic neurons in substantia nigra Selective loss of serotonergic neurons in dorsale raphe Damages of amygdala

23. Cell loss in AD brains and MD (in lifetime) LCSNDR Zweig et al, 1988(n=25)Yes Zubenko et al, 1988(n=14/37)YesYes Förstl et al. 1992 (n= 14/52)YesNo- Hoogendijk et al, 1999(n= 12/26)No-- Hendricksen et al, 2004(n = 7/14)--No LC = Locus coeruleus (Noradrenergic) SN = Substantia nigra (Dopamin) DR = Dorsale raphe (Serotonin)

25. Lewy bodies

27. Lewy bodies and MD in AD of mild to moderate degree Score 1-2 = mostly brainstem Score 3-6 = mostly limbic structures Score 7-10= mostly neocortical structures (all positive cases also had LB in amygdala) Lopez et al. Neurology 2006; 67: 660-5.

28. Why high persistence rate and poor prognosis? Due to treatments Not treated Treated with drugs with too low dosages? Drugs not effective? Due to our conception of depression in dementia? Typical symptoms Heterogeneity Various risk factors Psychological or biological factors Similarities and interaction between depression and AD Hippocampus atrophy Vascular factors Inflammatory processes AD pathology

29. Typical MTLA in AD

30. Reduced hippocampus volume in early and late onset depression Hickie et al. Br J Psychiatry 2005; 186: 197-202

31. Hippocampus atrophy in recurrent MD (n=10+10) Sheline Y et al. Proc Natl Acad Sci 1996; 93: 3908-13

32. Hippocampus atrophy in recurrent MD Sheline Y et al. Proc Natl Acad Sci 1996; 93: 3908-13

33. Depression, hippocampal volume and cognition in elderly above 60 years of age MD (DSM-IV; n=61) vs Controls (n=40) Hippocampus volume, rp< 0.04 Hippocampus, volume, lp 0.23 Whole brain volumep 0.75 Salivary cortisol p< 0.001 Memoryp< 0.001 Attentionp< 0.001 Executive functionp< 0.001 Within the depressed subjects no correlation was found between hippocampus volume and salivary cortisol level O’Brien et al. Am J Psychiatry 2004; 161: 2081-90

34. Vascular factors

35. Cardiovascular factors and risk for depression Almeida et al. Am J Geriatr Psychiatry 2007; 15: 506-13.

36. Risk factors for late onset depression Hypertension Diabetes Hyperhomocysteinemia Obesity Smoking Diet (omega 3 fatty acid) Lack of exercise Socioeconomic class

37. Risk factors for late onset AD Very well established High age Genetic polymorphism (ApoE e4) Established Hypertension Hypercholesterolemia Hyperhomocysteinemia Obesity Smoking Diet (3 omega fatty acid) Lack of exercise Lack of education/socioeconomic class Head injury

38. Late life depression and cytokines Cytokines as chemical messengers between immune cells and endothelial cells, playing a key role in mediating immune and inflammatory responses which can lead to neurochemical (serotonin), neuroendocrine (HPA axis) and behavioural effects (depression)  The pro-inflammatory cytokines IL-6 (strongest), IL-1 beta, CRP and TNF alpha are increased in depression (also in LO depression)  The anti-inflammatory cytokines IL-4; IL-10 and IL-13 are decreased in depressed patients, (uncertain in LO depression) Craddock and Thomas. Essent Psychopharmacol 2006; 7(1): 42-52.

39. Aging Neurotransmitters’ deficits Micro- & astroglia activation Inflammation Cognitive dysfunction Oxidative stress APP & presenilin mutations Increased A  production Tau protein hyperphosphorylation Synaptic damage Neurodegeneration Neuronal death Apoptosis Mitohondrial dysfunction Ca++ homeostasis APOE Plasma cholesterol

41. IL-6 (45 AD, 34 MCI patients and 28 Controls) Bermejo et al. Immunology Letters 2008; 117: 198-202

42. TNF-alpha Bermejo et al. Immunology Letters 2008; 117: 198-202

43. Inflammation in Depression and dementia/AD DepressionDementia/AD Pro-inflammatory cytokines IL-1++ IL-6++ TNF- alpha++ IFN++ Anti- inflammatory cytokines IL-4-/??/- IL-10-/??/- Leonard B. Neurochem Res 2007; 32: 1749-56

44. Possible link between chronic depression and dementia Leonard B. Neurochem Res 2007; 32: 1749-56

45. Conclusions and future directions. Depression in dementia is a heterogeneous condition that in about 50% of the cases is of chronic nature. Because of weak evidence for treatment effect new studies (observational and treatment) should be carried out with: Larger sample Alternative outcome as, “sadness +¨, and cluster of symptoms There is an overlap of symptoms, common risk factors, and common biological findings in AD and depression. The mechanism behind these common denominators should be further explored: Structural brain damages Vascular factors Inflammatory processes