Um princípio de Alzheimer... Alexandre de Mendonça

1. Um princípio de Alzheimer... Alexandre de Mendonça Serviço de Neurologia e Laboratório de Neurociências, Faculdade de Medicina da Universidade de Lisboa e Instituto de Medicina Molecular

2. there are currently over 6 million people with dementia in the European Union and it is predicted that this number will double in the next 20 years estimate of the cost of dementia in the European Union amounts to €130 billion with €57.3 billion in direct costs and €72.7 billion in informal care costs borne by families and carers

3. the patient initially presented at fifty-one years of age… progressive memory loss soon followed…

4. Tem queixas acerca da sua memória? • Já lhe disseram que o(a) acham esquecido(a)? • Esquece com frequência nomes de pessoas da família ou de amigos? • Esquece-se frequentemente onde põe as coisas? • Costuma tomar apontamentos para não se esquecer das coisas? • A conversar costuma ter dificuldades em encontrar as palavras? • Já alguma vez se perdeu perto de sua casa? • Acha que anda a pensar mais devagar do que antes? • Sente que as suas ideias por vezes ficam confusas (baralhadas)? • Tem tido dificuldade em concentrar-se? (Schmand et al., 1996, adapted by Ginó, 2000)

5. Number of participants (n) 292 Age [years, mean±s.d. (range)] 50.5 ± 17.1 (18-87) Decades (years) 18-29 (n) 38 30-39 (n) 49 40-49 (n) 48 50-59 (n) 56 60-69 (n) 55 >70 (n) 46 Gender (female/male) 153/139 Education [years, mean±s.d. (range)] 9.7 ± 4.7 (2-20) MMSE [mean±s.d. (range)] 28.9 ± 1.2 (25-30) CVLT (LDFR) [mean±s.d. (range)] 11.5 ± 2.6 (4-16) SMC [mean±s.d. (range)] 4.5 ± 3.3 (0-14) Depressive Symptoms (n) 46 (Mendes et al., Aging Mental Health, 2008)

6. % 63.8 39.0 13.3 40.0 56.2 68.6 2.9 35.2 29.5 39.0 • Tem queixas acerca da sua memória? • Já lhe disseram que o(a) acham esquecido(a)? • Esquece com frequência nomes de pessoas da família ou de amigos? • Esquece-se frequentemente onde põe as coisas? • Costuma tomar apontamentos para não se esquecer das coisas? • A conversar costuma ter dificuldades em encontrar as palavras? • Já alguma vez se perdeu perto de sua casa? • Acha que anda a pensar mais devagar do que antes? • Sente que as suas ideias por vezes ficam confusas (baralhadas)? • Tem tido dificuldade em concentrar-se? (Schmand et al., 1996, adapted by Ginó, 2000, Mendes, 2003)

7. Maria da Luz _____ que reside em Lisboa ____ no Bairro Alto ____ e trabalha ___ como mulher de limpeza ___ num edifício comercial, queixou-se _____ na esquadra de polícia _____ do Rossio _____ de ter sido assaltada _____ e roubada _____ em 5 contos _____ na Avenida da Liberdade _____ na noite anterior _____. Tem 4____ filhos pequenos _____ que não comem _____ há 2 dias _____ e a renda da casa _____ por pagar _____. O chefe da polícia _____, comovido com a história desta mulher _____ organizou um peditório ____ em seu favor ____. no correlation between SMC score and Logical Memory score (Wechsler Memory Scale, adapted by Garcia, 1984)

8. CVLT 1 2 3 4 5 short long Broca Ameixas Colete Salsa Uvas Colorau Camisola Chave parafusos Cebolas Tangerinas Serrote Casaco Noz moscada Damascos Alicate Calças (Delis et al., 1987, adapted by Baeta, 2002) no correlation between SMC score and CVLT (LDFR) score

9. Number of participants (n) 946 Age [years, mean±s.d. (range)] 54.2 ± 20.1 (18-92) Age Groups (years) 18-29 (n) 191 30-39 (n) 59 40-49 (n) 95 50-59 (n) 136 60-69 (n) 198 70-79 (n) 205 ≥80 (n) 62 Gender (female/male) (%) 569/377 (60.1/39.9) Education [years, mean ± s.d. (range)] 8.2 ± 4.9 (0-19) 0 44 1-4 365 5-11 236 ≥12 301 Depressive Symptoms (n) (%) 228 (24.1) (Ginó et al., Gerontology 2009)

10. Scores of item 1 (Do you have complaints concerning your memory?) and 9 (Do your thoughts ever become confused?) significantlyincreased with age Scores in items 2 (Do other people find you forgetful?) and 5 (Do you often use notes to avoid forgetting things?) significantly decreased with age (Ginó et al., Gerontology 2009)

12. P., male, 75 years old, medical doctor For the last 2 years: Loses the pocketbook, the glasses Forgets the names of people Writes messages not to forget what is told The consultations take longer, must record every detail Studies very hard to retain some information

13. L., male, 75 years old, medical doctor CT scan, blood analysis: Normal Neuropsychological examination: Moderate deficit of logical memory Other domains are maintained

14. Questions: - Is this the ageing process or the beginning of Alzheimer’s disease? - What can we do about it?

15. Diagnosis of MCI * memory complaint (corroborated by informant) * normal activities of daily living * normal general cognitive function * abnormal memory for age and education * not demented (Petersen et al., 1999)

16. Diagnosis of MCI * cognitive complaint (from the patient or family) * no major repercussions on daily life, may have difficulties on complex activities * report a decline in cognitive functioning relative to previous abilities during the past year * impairment in memory and/or other cognitive domain * no dementia (European Consortium on Alzheimer’s Disease JNNP 2006)

17. (Ribeiro et al., J Clin Exp Neuropsychol 2007 29 187-197 )

18. (Ribeiro et al., 2006 Dementia Cogn Geriatr Dis 21:284-290 )

19. (Ribeiro et al., 2006 Dementia Cogn Geriatr Dis 21:284-290 )

20. MCI – evolution 28.9% progressed to dementia in 2 years (Ribeiro, PhD thesis )

21. Questions: - Is this the ageing process or the beginning of Alzheimer’s disease? - You have Mild Cognitive Impairment. - (!!??…..)

22. MCI – evolution some patients do not evolve after many years… (Ribeiro, PhD thesis )

23. (Nunes et al., J Alzheimer Dis 2009)

24. (Nunes et al., J Alzheimer Dis 2009)

25. * MCI pre-MCI control (n=40) (n=30) (n=24)

26. “Pre-MCI” A 68-year-old woman developed progressive language difficulties, gait disturbance, and a marked asymmetric right parkinsonian syndrome. At baseline, neurological examination had showed gait difficulties related to degenerative lumbar spinal stenosis.The diagnosis of frontotemporal lobar degeneration was established. A 76-year-old woman had increasing cognitive decline and difficulties with daily living activities, and went to a nursing home with the diagnosis of Alzheimer’s disease. (Nunes et al., J Alzheimer Dis 2009)

27. (Nunes et al., J Alzheimer Dis 2009)

28. Questions: - Is this the ageing process or the beginning of Alzheimer’s disease? - You have Mild Cognitive Impairment. - It looks as Alzheimer’s disease after all ….

30. Alzheimer’s disease APP tau b-amyloid

31. MCI - progression to Alzheimer’s disease Neuropsychological test Univariate estimated predictive accuracy % (CI) Symbol Digit Modalities test 70.7 (0.699-0.717) NYU Delayed Paragraph recall test 73.2 (0.718-0.739) ADAS-cog total score 73.7 (0.73-0.747) Delayed 10-Word List recall 73.5 (0.73-0.744) (Fleischer et al., 2007)

32. Consecutive series of patients with cognitive complaints and without dementia Cases with re-evaluation (n) follow-up (years) 400 2.3 Linear discriminant analysis Quadratic discriminant analysis Logistic regression Multilayer perceptrons Classification trees Probabilistic neural networks Radial basis function neural networks Support vector machines Random forests (Maroco et al., 2010)

33. (Maroco et al., 2010)

34. Prospective Memory. Mean proportion (and Confidence Intervals) of Actions Correctly Remembered at the Appropriate Moment in each Type of Cue-Action pair X Method of Encoding X Age condition (semantic relatedness reported by participants). (Pereira et al., submitted)

35. (Pereira et al, 2010)

36. ADCS/ADLMCI (Pedrosa et al., 2010, J Nutr Health Aging)

37. ADCS/ADLMCI Curva ROC para discriminação da ADCS MCI ADL18 entre Controlos e DCL Curva ROC para discriminação da ADCS MCI ADLFINAL entre Controlos e DCL (Pedrosa et al., 2010, J Nutr Health Aging)

40. MCI - progression to Alzheimer’s disease MRI of the hippocampus (volumetry) sensitivity specificity predictive value (correct classification) 61.3% 80% 78.9% (fixed) (Devanand et al., 2007)

41. Alzheimer’s disease APP tau b-amyloid

43. combination of CSF t-tau and Ab42 at baseline for detection of incipient AD in patients with MCI sensitivity specificity positive predictive negative predictive value value 95% 83% 81% 96%

44. (Gabriel Miltenberger, Sónia Pereira)

45. MCI - progression to Alzheimer’s disease (Frisoni and Caroli, 2007)

46. Apolipoprotein E 155 NH2 COOH 141 286 263

47. 3 hypothetical biomarkers z AD non-AD y x (modified from Small, 2001)

49. L., male, 80 years old, medical doctor Global decline in neuropsychological evaluation Hippocampal volume (total, not corrected) 5929.0 mm3 5389.5 mm3

50. The story five years after... Questions: - Alzheimer’s disease is already there, what can we do about it? - b-amyloid appears to cause neuronal damage, let us remove the b-amyloid