1. Current Trends in Alzheimer’s Disease
Brian Quinn DO
Geriatrics, Hospice and Palliative Care

3. Objectives Discuss early signs and symptoms of Alzheimer’s disease
Discuss the difference between dementia types
Bring up ways of initial evaluation and screening for cognitive impairment.
Answer the question, “What can be done to slow down or prevent dementia?”
Bring up current trends in dementia research

4. Disclosures I’m not paid by any pharmaceutical company
Some discussion is “off-label”
Information presented is from multiple sources and is “evidence-based” – there are a lot of alternative treatments that do not have good trials to show if they are effective or not.

7. Early Signs and Symptoms of Alzheimer’s Disease
The Alzheimer’s Association talks about the 10 signs of Alzheimer’s disease
1) Memory loss that disrupts daily life
2) Challenges in planning or solving
problems
3) Difficulty completing familiar tasks

8. Signs of Alzheimer’s
4) Confusion with time or place 5) Trouble understanding visual images and spatial relationships 6) New problems with words in speaking or writing 7) Misplacing things and losing the ability to retrace steps

9. Signs of Alzheimer’s
8) Decreased or poor judgment 9) Withdrawal from work or social activities 10) Changes in mood and personality All of these can be signs of dementia, so what’s the difference?

10. What is the Difference? Dementia Lewy-Body Frontotemporal Vascular
Parkinsons
Alzheimer’s Disease
other
Dementia

13. What is Dementia? Major impairment in learning and memory
One of the following:
Impairment in handling complex tasks
Impairment in reasoning ability
Impaired spatial ability and orientation
Impaired language

14. What is Dementia?
Impairments must significantly interfere with the individual’s work performance, usual social activities, or relationships with other people
Significant decline from previous level of functioning
Insidious onset and progressive (Alzheimer’s)

15. What is Dementia? Symptoms don’t occur exclusively during delirium
Not better accounted for by another illness
Depression
Hypothyroidism
Vitamin B12 deficiency
Medications or other substances
Hydrocephalus or brain lesion
Etc.

17. The Three Main Stages of Dementia
Mild or Early Stage
Memory loss and cognitive impairments are small but become increasingly noticeable
The person can cover up or make adjustments for these gaps and lapses, they continue to function independently
Signs and symptoms of this stage are often the result of stress or bereavement. In older people they may be the normal aging process

18. The Three Main Stages of Dementia
Moderate or Mild Stage
Memory lapses and confusion become more obvious and the person becomes more distressed by them
The person can no longer hide these from family and friends
Their personality and mental abilities may start to change and physical problems develop
The person needs more support to help them manage the tasks of daily of living
They may need repeated reminders and help to eat, wash, dress, and use the toilet

19. The Three Main Stages of Dementia
Severe or Late Stage
Individuals will become more severely disabled and need more help, gradually dependent on caregivers
Dementia may limit the person’s ability to communicate
Memory and personality will deteriorate further
They will need more assistance with daily tasks of bathing, dressing and eating. They may no longer be able to live independently

20. Types of Dementia Alzheimer’s disease 60 - 80 %
Lewy Body dementia – 15 %
Vascular dementia %
Parkinson’s dementia %
Frontotemporal dementia 2 – 5 %
Other < 2 % (alcohol, Pick’s disease, MS, etc.)

21. Alzheimer’s
Hallmark of Alzheimer’s is slow start with gradual progression over years
It is diagnosed by talking with the person and the family/friends
There is no blood test or study (MRI, etc.) that confirms Alzheimer’s, these rule out other causes
The only definitive diagnosis has been brain biopsy

22. Dementia with Lewy bodies
Fluctuations – often look like a stroke
Visual hallucinations
Parkinson’s-like features

23. Vascular Dementia Dementia Often step-wise after strokes or TIA’s
May be silent, but a brain scan (CT, MRI) shows many small areas of stroke
Often can be “mixed” with Alzheimer’s

24. Parkinson’s Dementia Dementia
Associated with more severe Parkinson’s disease
Differs from Lewy Body dementia
Often functional decline from Parkinson’s is much more significant than the “thinking” problems

25. Frontotemporal Dementia
Personality changes
Lack of insight
Socially inappropriate
Loss of empathy
Mental rigidity

26. What about Mild Cognitive Impairment? (MCI)
Memory difficulties but no problems with ability to function in daily life
Very common pre-cursor to dementia
This is where treatments have found the best benefit to delay rapid decline

27. Why is early detection important?

28. Early Detection Short term memory loss, i.e. frequent “senior moments”
Avoiding activities that were normally common
Problems with finances, getting lost, leaving the stove on, etc.
Wearing the same clothes and forgetting to change
Poor decision making – prone to financial abuse

29. Tools for Screening Saint Louis University Mental Status Exam (SLUMS)
Mini Mental Status Exam (MMSE)
Alzheimer’s Association Early Identification Tools
Memory Impairment Screen (MIS)
Mini-Cog
General Practitioner Assessment of Cognition (GPCOG)
Geriatric Depression Scale (GDS)

30. Summary of Screening SLUMS – 8 minutes, free, has scoring for MCI
MMSE – 8 minutes – cost money, less specific for MCI
MIS – less than 5 minutes – simple scoring, all verbal
GPCOG – less than 5 minutes – uses informant to help with half the test
Mini-Cog – less than 5 minutes – very simple screen with 2 components

31. Testing for cognitive impairment
Patient and family interview
Physical Exam
Mental Status and depression assessment
Labs: CBC, Glucose, serum electrolytes, BUN/creatinine, TSH, Drug levels (e.g. digoxin), liver function tests, B12 and folate levels, VDRL, Calcium
CT scanning without IV contrast – detects hydrocephalus, mass lesions, ischemic changes

32. What Can We Do? Antioxidant vitamins (E, C, A) - don’t help
growing number of studies show this
Vitamins B6, B12, folate – only help if deficient
Vitamin D – may help a little
Fish oil (omega-3 fatty acids) – may have some benefit, still in trials, several negative trials out
Ginkgo Biloba – doesn’t help
Nutriceuticals – see magazines and newspaper ads – lack evidence, often financial scams

33. Current Medical Treatments
Helps a little, only at higher doses
Early treatment more promising
Only 5 medications in 2 classes that are FDA approved
Delays, doesn’t prevent
Not very effective in moderate to severe dementia
Often the side effects are limiting

34. FDA Approved Medications
Cholinesterase Inhibitors
* tacrine (Cognex) - * no longer available
galantamine (Razadyne and Razadyne ER)
donepezil (Aricept)
rivastigmine (Exelon and Exelon Patch)
N-methyl-D-asparate (NMDA) receptor antagonist
memantine (Namenda and Namenda XR)

36. Current Trends in Dementia Research
Biomarkers for early detection
Brain imaging
Body proteins
Genetic risk profiling
Focus on mild cognitive impairment
Future Drugs

37. Biomarkers for Early Detection
Current diagnosis of Alzheimer's relies largely on documenting mental decline. We now know that Alzheimer's has already caused severe brain damage in individuals who meet the criteria for mental decline.
Researchers hope to discover an easy and accurate way to detect Alzheimer's before these devastating symptoms begin. Experts believe that biomarkers (short for "biological markers") offer one of the most promising paths. Biomarkers are reliable predictors and indicators of a disease process. Biomarkers include proteins in blood or spinal fluid, genetic variations (mutations) or brain changes detectable by imaging.

38. Brain Imaging for Early Detection
Structural Imaging
provides information about the shape, position or volume of brain tissue. Structural techniques include magnetic resonance imaging (MRI) and computed tomography (CT)
Functional Imaging
reveals how well cells in various brain regions are working by showing how actively the cells use sugar or oxygen. Functional techniques include positron emission tomography (PET) and functional MRI (fMRI)
Molecular Imaging Technologies – looks at beta amyloid deposits during PET scan
uses highly targeted radiotracers to detect cellular or chemical changes linked to specific diseases. Molecular imaging technologies include PET, fMRI and single photon emission computed tomography (SPECT). i.e. Pittsburgh compound B (PIB), 18F flutemetamol (flute), Florbetapir F 18 (18F-AV-45), Florbetaben (BAY )

39. PET scan

40. Body Protein Analysis Cerebrospinal fluid (CSF) proteins
Research suggests that Alzheimer's disease in its earliest stages may cause changes in CSF levels of tau and beta-amyloid, two proteins that form abnormal brain deposits strongly linked to the disease.
Unfortunately, there is a lack of consistency from lab to lab that makes this unreliable
Proteins in blood or other parts of the body
Still in speculation

41. Genetic Risk Profiling
Scientists have identified three genes with rare variations that cause Alzheimer's and several genes that increase risk but don't guarantee that a person will develop the disease. Investigators worldwide are working to find additional risk genes. As more effective treatments are developed, genetic profiling may become a valuable risk assessment tool for wider use.

42. Genetic Testing for APO-e4
The strongest risk gene
Included in some clinical trials to identify participants at high risk for the disease
APOE-e4 testing is not currently recommended outside research settings because there are no treatments yet available that can change the course of Alzheimer's

43. Focus On Mild Cognitive Impairment
Increased risk of developing Alzheimer's disease within a few years; research surrounding MCI offers another potential path to earlier diagnosis.
Individuals with MCI have a problem with memory or another mental function serious enough to be noticeable to themselves and those close to them and to show up on mental status testing. These problems, however, are not severe enough to interfere with daily activities, so the person does not meet current diagnostic guidelines for Alzheimer's.
While individuals with MCI often go on to develop Alzheimer's disease, this is not always the case. In some people, MCI never gets worse. In others, it eventually gets better.

44. Targets for Future Drugs
Beta-amyloid
Tau protein
Inflammation
Insulin resistance
Gauging treatment impact with brain imaging and biomarkers
Learning from families with rare Alzheimer-causing genetic changes

46. Beta-Amyloid Drug Research
The chief component of plaques, one hallmark Alzheimer's brain abnormality
This protein fragment is clipped from its parent compound amyloid precursor protein (APP) by two enzymes — beta-secretase and gamma-secretase
Researchers are developing medications aimed at virtually every point in amyloid processing
Blocking activity of both enzymes
Preventing the beta-amyloid fragments from clumping into plaques
Using antibodies against beta-amyloid to clear it from the brain

47. Tau Protein Drug Research
The chief component of tangles, the other hallmark brain abnormality
Researchers are investigating strategies to keep tau molecules from collapsing and twisting into tangles, a process that destroys a vital cell transport system.

48. Inflammation Drug Research
Key Alzheimer's brain abnormality
Scientists have learned a great deal about molecules involved in the body's overall inflammatory response and are working to better understand specific aspects of inflammation most active in the brain.
These insights may point to novel anti-inflammatory treatments for Alzheimer's disease.

49. Insulin Resistance Drug Research
Insulin may be linked to Alzheimer's disease
Researchers are exploring the role of insulin in the brain and closely related questions of how brain cells use sugar and produce energy
These investigations may reveal strategies to support cell function and stave off Alzheimer-related changes

50. Gauging Treatment Impact with Brain Imaging and Biomarkers
Many clinical trials in progress include various brain imaging studies and testing of blood or spinal fluid
Researchers hope these techniques will one day provide methods to diagnose Alzheimer's disease in its earliest, most treatable stages — possibly even before symptoms appear
Biomarkers may also eventually offer better methods to monitor response to treatment

51. Learning from families with rare Alzheimer-causing genetic changes
Another new approach to testing experimental drugs to be given before symptoms appear focuses on individuals with rare genetic mutations that guarantee they'll eventually develop Alzheimer's disease
All of these currently known mutations affect beta-amyloid processing or production

52. Important Points Alzheimer’s disease is best treated when caught early
Alzheimer’s affects more than memory
Alzheimer’s is the most common kind of dementia
Healthy living (diet, exercise, avoiding bad stuff, taking care of medical problems) is the best way to prevent dementia

53. Important Points
There are few current medical treatments for Alzheimer’s that have modest success
There are lots of areas of research in Alzheimer’s that look promising
Early detection works best for all facets of this disease!

54. Questions?
????

55. References
Alzheimer’s Association website ( and research center
Drug Utilization in Practice October 2013 “Ginkgo Biloba for Memory”
Journal of Alzheimer’s & Dementia 17 Dec “Alzheimer’s Association Recommendations for operationalizing the detection of cognitive impairment during the Medicare Annual Wellness Visit in a primary care setting”
UptoDate
Treatment of dementia
Cholinesterase inhibitors in the treatment of dementia
Genetics of Alzheimer disease
Risk factors for dementia
Clinical manifestations and diagnosis of Alzheimer disease
Evaluation of cognitive impairment and dementia
Prevention of dementia
Clinical features and diagnosis of dementia with Lewy bodies
Frontotemporal dementia: Clinical features and diagnosis
Parkinson disease dementia

56. Thank you!