1. ALZHEIMER’S DEMENTIA As I Understand it….
Bhagyashree Barlingay MD

2. PERSISTENCE OF MEMORY

3. Normal Ageing,
MCI- mild cognitive impairment,
Dementia.

4. Why Alzheimer’s Dementia?
320 Million elderly people in India above the age of 65.
Prevalance of AD million people
1 in 1,000 in age group years;
1 in 5 over the age of 80 years.
Incidence Of AD –
Doubles every 10years after the age of 60 years.
Cost of taking care of a dementia patient
Financial, social, mental, physical !
No cure yet!

5. COST OF DEMNTIA CARE

6. Focus of discussion 1. What is dementia?
2. What is the cause of dementia?
3. Can we prevent it?
4. Role of palliative and hospice care

7. स्मृती बुद्धी भ्रंश

8. What is dementia?
1. Progressive loss of memory, language, orientation, judgment, visuospatial abilities.
the commonest type is Alzheimer’s dementia (AD).
The course of AD a prolonged goodbye!

9. AD Progression
Healthy aging
Amnestic MCI
Clinically diagnosed AD
Progressive, irreversible brain disorder which is not a part of normal aging1
Insidious onset of early symptoms often mistaken for age-related memory change1
Disease progression leads to behavioral and cognitive changes1
Variable disease progression and rate of decline1
Risk factors: aging, family history1, head injury2
AD brain changes may start decades before symptoms show
Amnestic MCI: memory problems; other cognitive functions OK; brain compensates for changes
Cognitive decline accelerates after AD diagnosis
Normal age-related memory loss
Key points
As they age, some individuals may have problems with memory greater than expected for their age—this is termed mild cognitive impairment (MCI)1
Several subtypes of MCI have been identified; the subtype that features memory impairment most prominently is called amnestic MCI1
Approximately 80% of patients with MCI will progress to Alzheimer's disease (AD) within 6 years of diagnosis1
The best known characteristic of AD is memory loss, but other symptoms such as inability to process and organize information, decision and problem-solving difficulty, personality changes, hallucinations, delusions, depression, lack of impulse control, perceptual-motor difficulties, and physical problems become more pronounced as the disease progresses1
More than 95% of all AD cases occur in patients age 65 years and older, which is called late-onset AD (also called sporadic AD)2
There is no single gene that accounts for AD inheritability; mutations and polymorphisms in multiple genes and nongenetic factors are thought to contribute to late-onset AD2
The 4 allele of APOE is also a major risk factor for developing AD2
Mutations of the amyloid precursor protein (APP), presenilin-1, and presenilin-2 genes account for the rare incidence of early-onset familial AD in patients less than 65 years of age2
Elevated levels of BACE-1 are seen in traumatic brain injuries and ischemia, which may result in elevated levels of A3
References
1. US Department of Health and Human Services Progress Report on Alzheimer's Disease. NIH Publication Number ; 2007.
2. Rocchi A, Pellegrini S, Siciliano G, Murri L. Causative and susceptibility genes for Alzheimer's disease: a review. Brain Res Bull. 2003;61(1):1-24.
3. Cole SL, Vassar R. The Alzheimer's disease beta-secretase enzyme, BACE1. Mol Neurodegener. 2007;2:22.
Total loss of independent
function
Birth 40 60 80
Death
Life Course
MCI=mild cognitive impairment.
1. US Department of Health and Human Services Progress Report on Alzheimer's Disease, 2007.
2. Van Den Heuvel C, et al. Prog Brain Res. 2007;161:

10. Progressive Decline in AD

11. Who used to live in this house? ---Cognition
1. Attention, 2. Memory, 3. Judgement, 4. Reasoning, 5. Language,

12. An Abandoned House

13. Assessment Scales MMSE – Dx, F/up, response to Rx.
KFSS – placement in a facility
FAST- used by hospice /medicare

16. KARNOFSKY PERFORMANCE STATUS SCALE
100 - Normal; no complaints; no evidence of disease.
90 - Able to carry on normal activity; minor signs or symptoms of disease.
80 - Normal activity with effort; some signs or symptoms of disease.
70 - Cares for self; unable to carry on normal activity or to do active work.
60 - Requires occasional assistance, but is able to care for most of his personal needs.
50 - Requires considerable assistance and frequent medical care.
40 - Disabled; requires special care and assistance.
30 - Severely disabled; hospital admission is indicated although death not imminent.
20 - Very sick; hospital admission necessary; active supportive treatment necessary.
10 - Moribund; fatal processes progressing rapidly.
0 - Dead

18. What are the risk factors for AD?
Non-modifiable-
Age, female gender, APOE genotype, family history.
Modifiable- (mostly overlapping with Vascular dementia)
Hypertension, type II DM, high cholesterol, metabolic syndrome, head injury, cerebrovascular disease, CKD, alcohol, depression, anemia.
Inconclusive-
High homocysteine , dietary fat, estrogen, hearing loss, Vitamin D deficiency.

19. Brain healthy diet-
Veges- arugula, broccoli,brussels sprouts,boc choy, cabbage,cauliflower,kale, turnip, spinach,eggplant,corn,bell peppers.
Fruits-berries, cherries, grapes,red grapes, oranges,plums, prunes.
Fish- tuna salad – minimum mayo,halibut,grilled or smoked salmon,sardines.
Drinks- green tea, pomegranate juice, red wine

20. HaLad- curcumin Anti-inflammotory, Anti-cancer, Anti-amyloidogenic;
But….

21. Alcohol- 4 oz glass of table wine -14 gm of alcohol
12 oz bottle of american beer gm of alcohol,
1.5 oz of 80-proof liquor in a mixed drink-18 gm of alcohol.
2 chemical- resveratrol and quercetin

22. What is metabolic syndrome?
A cluster of risk factors for cardiovascular diseases including abdominal obesity, high triglycerides, low HDL,HTN, type II DM.

23. Why is Metabolic syndrome linked to AD?
1. High insulin levels are linked to cognitive decline.
2. Insulin degrading enzyme (IDE) helps take care of beta-amyloid as well along with insulin.
3. IDE levels are low in type II dm.
4. IDE has more affinity for insulin.

24. How does one decrease the risk of AD by acting on the modifiable risk factors?
CHANGE YOUR LIFESTYLE….

26. What is Lifestyle?
Lifestyle - social, mental, and physical activity - inversely associated with the risk for Alzheimer’s disease (AD).
Midlife levels of cardio-respiratory fitness may predict risk of dementia later in life, independent of cerebro-vascular disease.

27. Why would lifestyle modification affect the risk of Dementia?
Three biologically plausible hypotheses have emerged –
The cognitive reserve hypothesis
The vascular hypothesis
The stress hypothesis 

28. The cognitive reserve hypothesis
The cognitive reserve hypothesis suggests that mental activity, learning, and social interaction prevent or reduce cognitive deficits by activating brain plasticity and enhancing synaptogenesis and perhaps neurogenesis. 

29. The vascular hypothesis
The vascular hypothesis suggests that social, mental, and physical activity prevents AD through reduction of cardiovascular disease and stroke.

30. The stress hypothesis
The stress hypothesis suggests that active individuals have more positive emotional states and reduced stress.

31. Stress Stress Down regulation of Hippocampal steroid receptors
Dampening of negative feedback control of the adrenocortical axis 
 resulting in high cortisol levels, hippocampal atrophy, and impaired cognition.

32. The storage of memory
Medial Temporal Lobe

33. Role Of Education in AD
Advanced Education >>> Higher cognitive reserve >>>Decreased impact of AD (not protection)
Cognitive Activities in late life delay the onset of Dementia
Normal Cognition premortem>>>on Autopsy , heavy AD pathology>>>but hypertrophic hippocampal neurons>>>higher language ability scores during life with advanced education.

34. Pathology of AD
Amyloid plaques
Neurofibrillary tangles

37. ,  Secretase Pathway: A Formation
Amyloid plaque
sAPP 
APP
Oligomers
 secretase A
 secretase
Key points
References
1. Wiltfang J, Esselmann H, Cupers P, et al. Elevation of beta-amyloid peptide 2-42 in sporadic and familial Alzheimer's disease and its generation in PS1 knockout cells. J Biol Chem. 2001;276(46):
2. Turner PR, O'Connor K, Tate WP, Abraham WC. Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol. 2003;70(1):1-32.
3. Maggio JE, Stimson ER, Ghilardi JR, et al. Reversible in vitro growth of Alzheimer disease beta-amyloid plaques by deposition of labeled amyloid peptide. Proc Natl Acad Sci U S A. 1992;89(12):
4. DeMattos RB, Bales KR, Parsadanian M, et al. Plaque-associated disruption of CSF and plasma amyloid-beta (Abeta) equilibrium in a mouse model of Alzheimer's disease. J Neurochem. 2002;81(2):
5. Tseng BP, Esler WP, Clish CB, et al. Deposition of monomeric, not oligomeric, Abeta mediates growth of Alzheimer's disease amyloid plaques in human brain preparations. Biochemistry. 1999;38(32):
6. Ling Y, Morgan K, Kalsheker N. Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer's disease. Int J Biochem Cell Biol. 2003;35(11):
7. US Department of Health and Human Services Progress Report on Alzheimer's Disease. NIH Publication Number ; 2007.
AICD
Cleavage is catalyzed by  and  secretases
The  cleavage site is within the transmembrane

39. AD Progression
Healthy aging
Amnestic MCI
Clinically diagnosed AD
Progressive, irreversible brain disorder which is not a part of normal aging1
Insidious onset of early symptoms often mistaken for age-related memory change1
Disease progression leads to behavioral and cognitive changes1
Variable disease progression and rate of decline1
Risk factors: aging, family history1, head injury2
AD brain changes may start decades before symptoms show
Amnestic MCI: memory problems; other cognitive functions OK; brain compensates for changes
Cognitive decline accelerates after AD diagnosis
Normal age-related memory loss
Key points
As they age, some individuals may have problems with memory greater than expected for their age—this is termed mild cognitive impairment (MCI)1
Several subtypes of MCI have been identified; the subtype that features memory impairment most prominently is called amnestic MCI1
Approximately 80% of patients with MCI will progress to Alzheimer's disease (AD) within 6 years of diagnosis1
The best known characteristic of AD is memory loss, but other symptoms such as inability to process and organize information, decision and problem-solving difficulty, personality changes, hallucinations, delusions, depression, lack of impulse control, perceptual-motor difficulties, and physical problems become more pronounced as the disease progresses1
More than 95% of all AD cases occur in patients age 65 years and older, which is called late-onset AD (also called sporadic AD)2
There is no single gene that accounts for AD inheritability; mutations and polymorphisms in multiple genes and nongenetic factors are thought to contribute to late-onset AD2
The 4 allele of APOE is also a major risk factor for developing AD2
Mutations of the amyloid precursor protein (APP), presenilin-1, and presenilin-2 genes account for the rare incidence of early-onset familial AD in patients less than 65 years of age2
Elevated levels of BACE-1 are seen in traumatic brain injuries and ischemia, which may result in elevated levels of A3
References
1. US Department of Health and Human Services Progress Report on Alzheimer's Disease. NIH Publication Number ; 2007.
2. Rocchi A, Pellegrini S, Siciliano G, Murri L. Causative and susceptibility genes for Alzheimer's disease: a review. Brain Res Bull. 2003;61(1):1-24.
3. Cole SL, Vassar R. The Alzheimer's disease beta-secretase enzyme, BACE1. Mol Neurodegener. 2007;2:22.
Total loss of independent
function
Birth 40 60 80
Death
Life Course
MCI=mild cognitive impairment.
1. US Department of Health and Human Services Progress Report on Alzheimer's Disease, 2007.
2. Van Den Heuvel C, et al. Prog Brain Res. 2007;161:

40. Trajectory of Cancer Vs.. Dementia

41. END OF THE LIFE ISSUES COMPLICATIONS OF AD
AGGRESSIVE TREATMENT AND CONSEQUENCES
CARDIO-RESPIRATORY RESUSCITATION
PROLONGATION OF LIFE
EDUCATION OF THE FAMILY

42. To do list….. 1 Make dementia a national priority
2 Increase funding for dementia research
3 Increase awareness about dementia
4 Improve dementia identification and care skills
5 Develop community support
6 Train caregivers
7 Develop comprehensive dementia care models
8 Develop new National Policies and Legislation, specially regarding end of the life issues.
9 Recommended books---

45. We are running out of time ---