Alzheimer disease new treatment trends

1. NEW TREATMENT TRENDS IN
ALZHEIMER DISEASE
GUIDE: DR.APOORVA PAURANIK
CANDIDATE: DR.SARATH MENON.R
Dept. of Neurology,
MGM MEDICAL COLLEGE,INDORE

2. OUTLINE
 Treatment of AD
 Treatment of secondary symptoms
 Experimental therapy
 Dietary measures
 Social support
 Prevention

3. ALZHEIMER DISEASE
 Most common cause for dementia
 24 milions has the disease at present
 Incidence doubles every 5 yr after age of 60.

4. RISK FACTORS FOR ALZHEIMER’S DISEASE
 Age
 Family history
 Lifestyle
Physical exercise
Mental exercise
Diet
Tobacco
Head injury
 Hypertension
 Elevated serum cholesterol
 Elevated serum homocysteine

5. PATHOPHYSIOLOGY
 Beta amyloid plaques
 Neurofibrillary tangles (NFT)
 Amyloid formed from APP (amyloid precursor
protein) by secretase
 NFT - silver stained fibrils of abnormally
phosporylated Tau protein

8. BIOCHEMICAL CHANGES
 Decrease in cortical level of Acetyl choline,choline
acetyl transferances,nicotinic receptors
 Degeneration of cholinergic neurons in nucleus
basalis of Meynert.
 Degenertion of loculus ceruleus & dorsal raphe
- noradrenergic & serotonergic depletion

10. CASCADE OF MECHANISM
Amyloid
inflammation
abnormal tau phosphorylation
free radical toxicity
synaptic loss

11. CASCADE OF MECHANISM
cholinergic dysfunction
neuronal loss
norepinephrine dysfunction
serotonergic dysfunction

12. CURRENT TREATMENT

13.  Symptomatic
- Cognitive
- Behavioral

14. TREATMENT OF MILD-MODERATE AD
 Choline esterase inhibitors
- Donepezil
- Rivastigmine
- Galantamine
 Improves cognition & daily activities

15. TREATMENT OF SEVERE AD
 NMDA antagonists
- Memantine
 Slows intracellular Ca accumulation and delay
nerve damage
 Used in combination with Donepazil

16. DOSAGE
 Donepezil – 5mg/day x 4-6 wks,then 10mg/d to
max.tolerated dose. min dose-5mg/d
 Rivastigmine – 1.5mg bd,then step up monthly to
6mg bd(max). min.dose-6mg/
 Galantamine- 8mg/d,monthly increase to 16mg/d
24 mg/d (max). min dose- 16mg/d
 Memantine – 5mg daily,in a week then 5mg Bd
15mg/d- (5 & 10), max dose-10mg bd

17. CURRENT AVAILABLE THERAPY
characteristic DONEPAZIL RIVASTIGMIN
E
GALANTAMIN
E
MEMANTINE
Chemical class piperidine carbamate phenanthrenea
lkaloid
Similar to
amantadine
Primary
mechanism
AchE inh AchE inh AchE inh NMDA
antagonist
Other
mechanism
None None Nicotine
modulator
HT3 receptor
antagonist
Half life 70 h 90 min 7 h 70 h
Metabolism Hepatic Renal Hepatic Hepatic

22. Combined clinical trial data for the three licensed acetylcholinesterase inhibitors:
rivastigmine (♦), donepezil (▴) and galantamine (•) versus placebo (▪).
BULLOCK R BJP 2002;180:135-139
©2002 by The Royal College of Psychiatrists

24. CURRENT STATUS OF ACHE INHIBITORS
 Effective in 6 month & 12 month trials
 Early initiation of therapy
 Delay institutionalization
 Decrease troublesome behaviours

25. TREATMENT OF SECONDARY SYMPTOMS
 Behavioural intervention
 Neuroleptic agents
- FDA in 2005 black box warning for
atypical neuroleptics
- 2008 , haloperidol,chlorpromazine,
thioridazine included
-CATIE-AD study showed cognitive
decline with atypical neuroleptics
-recommended in low doses in frail,
elderly

26.  Antidepressants & mood stabilizers
-citalopram ( Nyth et al study)
- 20 mg /day in elderly ,max-40mg
- sertaline & fluvoxetine – no benefits
(Wintraub & Petrecca et al study)
- mirtazipine has no benefial effect
( Banerjee et al)
 Anticonvulsants
- gabapentin,valproate can be used

27.  Anti inflammatory agents
- NSAIDs delay onset of AD
- Breitner et al showed NSAIDs don’t
protect against AD in very old
 A double blind,placebo controlled trial
( Grundman et al 2003)
showed rofecoxib & naproxen don’t delay AD
progression

28. EXPERIMENTAL THERAPY

29.  Anti amyloid therapy
- vaccination with amyloid species
- monoclonal anti amyloid antibodies
- IVIG containing amyloid binding antiboies
- selective amyloid lowering agents
- chelators of amyloid polymerization
- beta secretase inhibitors
 Till date no phase 3 trials for anti amyloid therapy
shown acceptable efficacy

30. VACCINATION
 Anti Abeta immunotherapy reduces amyloid
deposition and improved spatial cognition in mice
 Clinical trial in 298 patients with AD:18 developed
inflammatory meningoencephalitis: study halted
 Autopsy in one: “less amyloid than expected”
Orgogozo J-M et al Neurology 2003;61:46
Mathews P & Nixon R Neurology 2003;61:7

31. VACCINATION
 In subgroup of 30 patients, those who generated
Abeta antibodies had reduced disease progression
 Attempts being made to reformulate vaccine
 Passive immunization considered
Hock C et al.Neuron 2003;38:547
Wolfe MS. Nat RevDrug Discov 2002;1:859

32. ANTIBIOTICS FOR AD
 Higher than normal titres of Chlamydia in people
with AD
 Multicentre Canadian double blind placebo
controlled RCT
 101 patients with mild to moderate AD (MMSE 11-
25)
 Daily doxycycline 200mg plus rifampin 300mg or
placebo for 3 months

33. ANTIBIOTICS FOR AD
 Standardized ADAS Cog @ 6 months difference
of 2.75/70 between treated and placebo group
(significant @ 6 but not 12 months)
 Standardized MMSE score 2.2/30 higher @12
(but not 3 or 6) months
 Intriguing results!
 Larger study in planning stages
Loeb M, Molloy DW et al JAGS 2004;52:381

34. SECRETASE INHIBITORS
 Inhibit production of Amyloid
 Tarenflurbil and Semagacestat.
 Two placebo controlled trials showed no efficacy

35.  Reversal of excess Tau phosphoryation
 Free radical scavengers
- vitamin E – reduce oxidative stress
- high dose Vit E (2000U/day) for 2 yr slowed
progression of AD ( large double blind
placebo trial ,Sano etal 1997)
- Alzheimer Disease Cooperative Study ( 769 pts)
showed no benefit vs placebo (Peterson etal 2005)
- cause cardiovascular side effects
- not recommended currently

36.  Estrogen replacement therapy
- postmenopausal woman
- RCT with 351 pts for 2 weeks showed no
beneficial effects
 Cholesterol lowering agents
-no beneficial effects
- RCT,double blinded study with 748 pts
for 6 months failed to prove efficacy

37. LIPID LOWERING AND AD
 Previous observations suggested lower risk of AD in
those taking “statins”
 Recently presented at 8th International Symposium on
Advances in AD therapy
 Atorvostatin treatment associated with less decline in
memory, function, mood & behaviour in people with AD
 Premature to decide until full details available in peer
reviewed publication

38. ONGOING TRIALS
 Tramiprosate (Alzhemed)
- homotaurine
- binds to soluble & insoluble Abeta and
in reduction
- protect against amyloid neurotoxicity
- reduce tau abnormal phosphorylation
 RCT, double blind,placebo conrolled trial (2009)

39.  Cerebrolysin
- peptidergic drug from purified pig brain
- neurotrophic & neuroprotective
 RCT,double blind, placebo controlled trial (2010)
 Latreperidine(Dimebom)
- anti histamine
- inhibit burylcholine esterase, AchE,
NMDA signalling pathway
RCT, phase 3 trial ongoing ( jan 2011)

40. CLINCAL TRIALS - COMPLETED
 Selegelline
RCT trial conducted in 2010 failed to give
promising results
 Nimodipine
- prevent Ca accumulation in neurons
- cause vasodilation
- RCT in March 2010 in 500 pts showed
positive results
- given 90mg/d & 180mg/d for 12,24,52 weeks
- improves cognition & global impression

41.  Metal protein attenuating compound(MPAC)
(clinoquinol)
- solubilize & clearance of Abeta
- RCT,double blind study with 36 pts
has no change in ADAS Cog @ 36 wks.
 Mertrifonate
- irreversible AchE inhibitor
- RCT, double blinded phase 3 study
- 60-80mg/d for 26 weeks showed improvement
MMSE-1.86/30 & ADASCog- 3.24/70

42.  Lecithin
- major source of choline
- RCT,double blind placebo controlled study
failed to show efficacy

43.  Huperzine A
from chinese club moss Huperzia serrata
reversible AchE inhibitor
RCT, double blinded Chinese study with
482 pts showed improvement in
MMSE-2.8/30 & ADASCog -1.91/70 @ 6 wks

44.  Transcutaneous electrical nerve stimulation
(TENS)
- change neurotransmitters,help in neuro
regeneration
- 3 RCT in Netherland & Japan
- duration,waveform,current amplitude,
- data limilted ,shows little improvement

45. STEM CELL THERAPY
 South Florida university with Cryo- cell International
 Mouse model study in 2009
 Several infusions of stem cells from umblical cord
 Myeloid protein reduced by 62%
 Cerebral amyloid angiopathy by 82%
 Hope to begin human trials by 2014.

46.  Neural growth factor (NGF)
-Injecting into spinal cord
- trials going to formulate oral preperation
- still on pipe line.

47. DIETARY MEASURES
 No special diet for AD
 Axona (caprylidine) improves cognition

48. PREVENTION OF AD
 Omega 3 fatty acids
- French study(2005) showed decrease in risk
of AD in elderly > 60 yr
- 2 RCT double blinded studies are ongoing
 Mediterranean diet
 Light to moderate alcohol
-Finnish study showed no beneficial effects

49. Who are the AD Caregivers?
• Spouses – the largest group. Most are older
with their own health problems.
• Daughters – the second largest group.
Called the “sandwich generation,” many are
married and raising children of their own.
Children may need extra support if a parent’s
attention is focused on caregiving.
• Grandchildren – may become major helpers.
• Daughters-in-law – the third largest group.
• Sons – often focus on the financial, legal, and
business aspects of caregiving.
• Brothers and Sisters – many are older with
their own health problems.
• Others-friends,relatives
Support for Caregivers
Slide 37

50. Technology and Caregiving
The NIA is studying how computers can
provide information and support to family
caregivers through:
These features have become very popular among users because
they reach many people at once, are private and convenient, and are
available around the clock.
• computer-based bulletin boards
• chat rooms
• Q & A modules
• medical advice forums
Support for Caregivers

51. CONCLUSION
 Most common dementing disease worldwide
 Pschyco-social,economic burden
 Current therapy is symptomatic and limited
 New clinical trials & treatment approaches on
pipeline
 Social support for caregivers & alzheimer support
societies .

52. REFERENCES
 Harrisons internal medicine – 18 th edition
 www.clinicaltrials.gov
 www.thecochranelibrary.com
 www.alzheimers.org
 www.alz.org
 www.nia.nih.gov

53. THANK U….