Understanding Dementia: What is it? Where does it come from?

1. Understanding Dementia: What is it? Where does it come from? David S. Geldmacher, MD, FACP Patsy and Charles Collat Endowed Professor of Neuroscience Department of Neurology UAB School of Medicine

2. I fear I am not in my perfect mind, Methinks I should know you, and know this man; Yet I am doubtful; for I am mainly ignorant what place this is; and all the skill I have Remembers not these garments; nor I know not where I did lodge last night (IV vii63) Shakespeare’s King Lear: Memory Loss in the Arts

3. Memory Loss most often is “learning problem” early on represents more than just memory problems Dementia loss of function due to change in thinking Symptom description (like “headache”) Alzheimer’s disease specific clinical syndrome specific pathological disorder Vocabulary IssuesComing to terms with the terms

4. Alzheimer’s Disease vs. DementiaUnderstanding the differences • Saying “dementia” is like saying “back pain” • It describes the symptoms • There are many causes of back pain • Pinched nerve, slipped disk, arthritis, fracture • There are many causes of dementia • Alzheimer’s disease is the most common cause in older people

5. Dr. Alois Alzheimer

6. Admitted to Frankfurt Asylum (Germany) 1901 at age 51, with inability to manage at home Mistrust of husband and female neighbor Mistakes in food preparation; neglected housework; could not find way around apartment; hid objects, then could not find them Memory and speech deficits Agitated, screaming, strikes other patients Became bedridden, developed bedsores, lost weight to 74 lbs. Died at age 55 in April 1906 Mrs. AugusteD. Dr. Alzheimer’s Original Patient

7. Dr. Alzheimer’s original findings

8. Alzheimer’s Disease: Research Progress 1900s– Dr. Alzheimer describes “A strange disease of the cerebral cortex” 1960s – Most “senile dementia” is found to have Alzheimer changes in the brain 1980s– Modern research diagnosis emerges, amyloid molecule is discovered 1990s– Mouse models of Alzheimer’s come out 2000s–Researchers find Alzheimer brain changes can be discovered before the first symptoms

9. What goes wrong in the brain to create memory loss in Alzheimer’s and Dementia? • Thoughts and memory come from electrical signals in a dense network of nerve cell branches. • Normal neurons have many branches and connection to others • Like trees in a dense forest • Alzheimer’s causes those connections to come apart http://www.freeimageslive.co.uk/free_stock_image/treebranchesjpg

10. Brain Cells (Neurons)From healthy to deceased http://www.newhorizons.org/neuro/diamond_brain_response.gif

11. Alzheimer pathologyUnder the microscope

12. Plaque and Tangles

13. Spatial processing Language Vision BehavioralRegulation Memory Human Behavior and AnatomyLateral Surface of the Brain

14. Location of Brain Tangles in AD = Regions of Highest Density Neurofibrillary Tangle Accumulation

15. Traditional viewAmyloid plaque damages brain cells http://flippies.com/adflipoff/wp-content/plugins/RSSPoster_PRO/cache/5ccdd_cells.jpg

16. New understanding of amyloidMaking amyloid is a normal process

17. New understanding of amyloidMaking amyloid is a normal process

18. Newer view:Amyloid damage begins before the plaque forms http://www.sciencenews.org/pictures/031211/alzheimers_illustration_zoom.jpg

19. New views on how amyloid leads to AD symptoms and brain cell death • Early onset AD is caused by genes that lead to too much amyloid production • These genes are found in less than 2% of all AD cases • No amyloid overproduction genes have been found for the other 98% of cases • Maybe the problem is removal not production • Excess amyloid may trigger the tangles to form • The plaque may be a byproduct of slow clearance and not the cause of the dysfunction • More than 30 genes that affect amyloid clearance have been linked to AD • The “slow drain” analogy (The same amount enters, but less leaves)

20. Looking for changes on MRI scanNeither plaque or tangles can be seen by MRI Front More brain loss in the memory centers (hippocampus) points strongly to AD

21. We can’t see the plaque or tanglesBut we can see their effects AD Normal Duara et al, Neurology 2008:71:1986-92

22. Research into Alzheimer’s Causes

23. Modern research is a cooperative effort that crosses many boundaries • Medical research on AD has exploded • In 1980 there were 104 scientific articles published on Alzheimer’s disease ; in 2013 there were 5178 • The effort is worldwide • About 300 scientists attended the First International Conference on AD in 1988 • Now, over 5000 scientists from more than 60 countries attend • The days of the lone brilliant scientist with the breakthrough cure are probably behind us

24. What are the root causes of Alzheimer’s ? How can we diagnose the disease better? How can we help people with the disease and their families? Branches of AD Medical Research

25. Genes create ‘enzymes’ Enzymes cause chemical reactions Make body structures (hair growth) Break down substances (like digestion) There is natural variety in enzymes Some people have “fast” enzymes Others have “slow” enzymes Genes and AD risk

26. Think of height variation in normal people Understanding variability in genes None of the heights are abnormal, they are just different

27. It is very likely that a person needs to have several “slow” genes to get AD The more slow genes, the earlier AD comes Lifestyle changes may counteract inefficient genes Lower blood insulin Antioxidants in food Exercise (physical and mental) Genetics

28. Finding Alzheimer’s disease earlier

29. Course of Alzheimer’s DiseaseTraditional view Healthy aging Mild Cognitive Impairment Mild AD Function Moderate AD Severe AD Time

30. New EvidenceAD damage starts years before memory loss

31. Seeing amyloid before forgetfulness begins • Pittsburgh Compound B • Binds to the amyloid • Very hard to use • Not in clinical use

32. FDG PET Seeing brain cell energy failure

33. Finding effective therapies

34. Understanding Treatment Effects No symptoms Symptoms evident Function Time

35. Understanding Treatment Effects Cure No symptoms Symptoms evident Function Initiate Therapy Time

36. Understanding Treatment Effects Cure No symptoms Symptoms evident Function Disease Arrest Initiate Therapy Time

37. Understanding Treatment Effects Cure No symptoms Symptoms evident Function Disease Arrest Slowed Progression Initiate Therapy Time

38. Understanding Treatment Effects Cure No symptoms Symptoms evident Function Disease Arrest Slowed Progression Initiate Therapy Symptomatic Benefit Time

39. Understanding Treatment Effects Cure No symptoms Symptoms evident Function Disease Arrest Combined Effect* Slowed Progression Initiate Therapy Symptomatic Benefit Time

40. Understanding Treatment Effects Prevention Asymptomatic Neuroprotection Initiate Therapy Symptomatic Delayed Onset Function Time

41. Current treatments • Current medicines help brain cells work better • They do not improve memory in most people • They do delay worsening of memory • They do help maintain independence • They do reduce caregiver burden • Current medicines do not restore brain cells or help them live longer • They do not prevent brain cell death • They do not reverse or remove amyloid accumulation Think of them like treating the fever, not the infection

42. New treatments • No new treatments have been approved since 2004 • There have been many treatment failures since then • Drugs to alter amyloid production • Drugs to prevent amyloid clumping • Drugs to reduce inflammation • Drugs to improve brain cell metabolism All have failed in human tests

43. The Alzheimer vaccine storyThe good news Vaccinating mice with amyloid removed plaque from brain Schenk D et al. Nature 1999;400:173-177

44. The Alzheimer vaccine storyThe bad news Vaccinating people with amyloid caused brain swelling and inflammation in 6% of the subjects In patients who did not get encephalitis, plaques were cleared from the brain, but dementia progression did not stop Bombois et al. Arch Neurol2007;64(4):583-7

45. Removing amyloid from the brain -2The good news – amyloid can be removed from the brain The bad news No effect on memory

46. Non-Drug Approaches

47. Most important elements of Quality of LifeAs reported by dementia patients Schölzel-Dorenbos et al. Aging Ment Health. 2010;14:113-9

48. Promoting well being through guided activity “Help those who are in search of activity and cannot find it.” -- Maria Montessori Courtesy Cameron Camp, PhD

49. Break activities into steps Emphasize closed-ended tasks Provide immediate positive feedback Emphasize action, not success Use habit memory Repetition Practice Find meaningful social roles Employ pleasant events Montessori-Based Activities Programming Concepts

50. If a person with dementia is engaged in a meaningful activity, the person cannot simultaneously be exhibiting problematic behavior. Montessori-based Activities Focus on Engagement Courtesy Cameron Camp, PhD