how to treat a case of AD

1. Treatment of dementia
Mohammed Mahdy, Msc

2. Senescence – a second childhood !
‫وجل‬ ‫عز‬ ‫هللا‬ ‫يقول‬(َ‫ف‬ ِ‫ث‬ْ‫ع‬َ‫ب‬ْ‫ال‬ َ‫ن‬ِ‫م‬ ٍ‫ب‬ْ‫ي‬َ‫ر‬ ‫ي‬ِ‫ف‬ ْ‫م‬ُ‫ت‬‫ن‬ُ‫ك‬ ‫ن‬ِ‫إ‬ ُ‫اس‬َّ‫ن‬‫ال‬ ‫َا‬‫ه‬ُّ‫ي‬َ‫أ‬ ‫َا‬‫ي‬َّ‫م‬ُ‫ث‬ ٍ‫ب‬‫ا‬َ‫ر‬ُ‫ت‬ ‫ن‬ِ‫م‬ ‫م‬ُ‫َاك‬‫ن‬ْ‫ق‬َ‫ل‬َ‫خ‬ ‫ا‬َّ‫ن‬ِ‫إ‬
ُ‫م‬ ِ‫ر‬ْ‫ي‬َ‫غ‬َ‫و‬ ٍ‫ة‬َ‫ق‬َّ‫ل‬َ‫خ‬ُّ‫م‬ ٍ‫ة‬َ‫غ‬ْ‫ض‬ُّ‫م‬ ‫ن‬ِ‫م‬ َّ‫م‬ُ‫ث‬ ٍ‫ة‬َ‫ق‬َ‫ل‬َ‫ع‬ ْ‫ن‬ِ‫م‬ َّ‫م‬ُ‫ث‬ ٍ‫ة‬َ‫ف‬ْ‫ط‬ُّ‫ن‬ ‫ن‬ِ‫م‬ْ‫ر‬َ ْ‫اْل‬ ‫ي‬ِ‫ف‬ ُّ‫ر‬ِ‫ق‬ُ‫ن‬َ‫و‬ ْ‫م‬ُ‫ك‬َ‫ل‬ َ‫ن‬ِ‫ي‬َ‫ب‬ُ‫ن‬ِ‫ل‬ ٍ‫ة‬َ‫ق‬َّ‫ل‬َ‫خ‬‫َا‬‫م‬ ِ‫م‬‫َا‬‫ح‬
ُ‫ش‬َ‫أ‬ ‫وا‬ُ‫غ‬ُ‫ل‬ْ‫ب‬َ‫ت‬ِ‫ل‬ َّ‫م‬ُ‫ث‬ ً‫ال‬ْ‫ف‬ِ‫ط‬ ْ‫م‬ُ‫ك‬ُ‫ج‬ِ‫ر‬ْ‫خ‬ُ‫ن‬ َّ‫م‬ُ‫ث‬ ‫ى‬ًّ‫م‬ َ‫س‬ُّ‫م‬ ٍ‫َل‬‫ج‬َ‫أ‬ ‫ى‬َ‫ل‬ِ‫إ‬ ‫اء‬ َ‫ش‬َ‫ن‬‫ن‬َّ‫م‬ ‫م‬ُ‫نك‬ِ‫م‬َ‫و‬ ‫ى‬َّ‫َف‬‫و‬َ‫ت‬ُ‫ي‬ ‫ن‬َّ‫م‬ ‫م‬ُ‫نك‬ِ‫م‬َ‫و‬ ْ‫م‬ُ‫ك‬َّ‫د‬
َ‫ت‬َ‫و‬ ً‫ئا‬ْ‫ي‬ َ‫ش‬ ٍ‫م‬ْ‫ل‬ِ‫ع‬ ِ‫د‬ْ‫َع‬‫ب‬ ‫ن‬ِ‫م‬ َ‫م‬َ‫ل‬ْ‫َع‬‫ي‬ َ‫ال‬ْ‫ي‬َ‫ك‬ِ‫ل‬ ِ‫ر‬ُ‫م‬ُ‫ع‬ْ‫ال‬ ِ‫ل‬َ‫ذ‬ْ‫ر‬َ‫أ‬ ‫ى‬َ‫ل‬ِ‫إ‬ ُّ‫د‬َ‫ر‬ُ‫ي‬َ‫ل‬َ‫ع‬ ‫َا‬‫ن‬ْ‫َل‬‫ز‬‫ن‬َ‫أ‬ ‫ا‬َ‫ذ‬ِ‫إ‬َ‫ف‬ ً‫ة‬َ‫د‬ِ‫م‬‫ا‬َ‫ه‬ َ‫ْض‬‫ر‬َ ْ‫اْل‬ ‫ى‬َ‫ر‬ْ‫ال‬ ‫َا‬‫ه‬ْ‫ي‬‫َاء‬‫م‬
ٍ‫يج‬ِ‫َه‬‫ب‬ ٍ‫ج‬ْ‫و‬َ‫ز‬ ِ‫ل‬ُ‫ك‬ ‫ن‬ِ‫م‬ ْ‫َت‬‫ت‬َ‫ب‬‫ن‬َ‫َأ‬‫و‬ ْ‫َت‬‫ب‬َ‫ر‬َ‫و‬ ْ‫ت‬َّ‫ز‬َ‫ت‬ْ‫اه‬)‫الحج‬5

3. Why we are treating dementia?
 What is the goal of treatment ?
 What is the future in treating dementia?

5. Dementia as a major health problem
 Dementia is a major public health concern
– Prevalence
– Chronicity
– Caregiver burden
– Financial costs
 There are no cures for the neurodegenerative dementias.
 5th leading cause of death in those 65+

6. Prevalence
 The higher prevalence in Latin America (8.5%),
 Lower prevalence in the four sub-Saharan African regions (2%–4%).
 A 35.6 million people lived with dementia worldwide in 2010, with
numbers expected to almost double every 20 years, to 65.7 million in
2030 and 115.4 million in 2050.
 In 2010, 58% of all people with dementia lived in countries with low or
middle incomes, with this proportion anticipated to rise to 63% in 2030
and 71% in 2050.
 Prince M. et al.; (2013): The global prevalence of dementia: A systematic review and metaanalysis,
Alzheimer's & Dementia Journal, 9: 63-75.

7. Global prevalence

8. North Africa and middle east
ALzhEIMER’S DISEASE INTERNATIONAL FACTShEET,
http://www.alz.co.uk/adi/pdf/prevalence. 2008

9. Zaitoun A.M., Sarhan A. M., Selim A. M. , Mousa G. R. (2008): Epidemiological
Study of Dementia after Retirement. Egypt J. Neurol. Psychiat. Neurosurg.,
45(1): 65-74.

10. Financial Cost
 The total estimated
worldwide cost of dementia
was US$ 604 billion in 2010.
About 70% of the costs occur
in Western Europe and North
America.

11. Directed cost

12. Mx – a team work
• Together

13. Mx – a team work
• Together
• Everyone

14. Mx – a team work
• Together
• Everyone
• Achives

15. Mx – a team work
• Together
• Everyone
• Achives
• More

17. Treatment of dementia
 Is it reversible or not?
 If reversible
 Treat the cause
 If not?
 Pharmacological
 Non pharmacological
 Interventional

18. Features suggesting reversibility
 Shorter duration of illness

19. Features suggesting reversibility
 Shorter duration of illness
 Subcortical type of dementia

20. Features suggesting reversibility
 Shorter duration of illness
 Subcortical type of dementia
 Younger age of onset

21. Features suggesting reversibility
 Shorter duration of illness
 Subcortical type of dementia
 Younger age of onset
 Prominent gait disturbance

22. Features suggesting reversibility
 Shorter duration of illness
 Subcortical type of dementia
 Younger age of onset
 Prominent gait disturbance
 Urinary dysfunction

23. Features suggesting reversibility
 Shorter duration of illness
 Subcortical type of dementia
 Younger age of onset
 Prominent gait disturbance
 Urinary dysfunction
 Focal neurological signs

24. General principles in pharmacotherapy
 One agent at a time
 Increase dose at 5-7 days interval
 Sedative side effects used to advantage
 Improving cognition not the only goal
 Treat ass. behavioural disorders
 High CNS side effects can occur in very old patients
 Modify according to stage, coast, compliance and comorbidities

26. The role of medications in the
management of dementia
1. Cure disease
2. Prevent disease or delay onset
3. Slow progression of disease
4. Treat primary symptoms eg memory
5. Treat secondary symptoms eg depression,
hallucinations

27. The role of medications in the
management of dementia?
1. Cure disease???
2. Prevent disease or delay onset??
3. Slow progression of disease
4. Treat primary symptoms e.g memory
5. Treat secondary symptoms e.g depression,
hallucinations

28. The role of medications in the
management of dementia?
1. Cure disease???
2. Prevent disease or delay onset??
3. Slow progression of disease
4. Treat primary symptoms e.g memory
5. Treat secondary symptoms e.g depression,
hallucinations

29. The role of medications in the
management of dementia?
1. Cure disease???
2. Prevent disease or delay onset??
3. Slow progression of disease
4. Treat primary symptoms e.g memory
5. Treat secondary symptoms e.g depression,
hallucinations

31. Pharmacological
 Cholinesterase inhibitors ( ChE-I)
 NMDA receptors antagonists
 Anti-oxidant drugs
 Anti-psychotic drugs
 New drugs

32. Therapeutic approaches based on
pathogenic mechanism
 Cholinergic deficiency
• Cholinesterase inhibitors FDA approved:
• Tacrine
• Donepezil
• Galantamine
• Rivastigmine

33.  The cholinesterase inhibitors have been extensively studied in AD, and their
efficacies as well as short- comings are well established. A Cochrane review
assessed pooled data from 7298 patients with AD treated with either
donepezil, rivastigmine, or galantamine at recommended doses. The
conclusion was that therapy with any of these drugs in patients with a
diagnosis of AD is associated with small but statistically significant
improvements in cognitive function, ADL, overall clinical condition, and
behavioral disturbances.

34. Ach E I
Tacrine
 A 30-week randomized control clinical trial showed a significant dose related
improvement in cognitive function However, subsequent studies were less
impressive and a short half-life, hepatotoxicity, and cholinergic side effects have
limited the use of this drug.

35. Ach E I
Donepezil
* Mild-mod-severe Alz dementia (MMSE 10-26); SL Rogers, Arch Intern Med, 1998
• Moderate to severe AD ( MMSE 5-17); H Feldman, Neurology, 2001
• Drug was shown to slow IADL and ADL decline; H Feldman, JAGS, 2003.
• Drug decreased the amount of time caregivers spent with the subject About
60min/day saved by the donepezil caregivers (was 124min/day); H Feldman,
JAGS, 2003.
 Mild-moderate Alzheimer’s dementia; AD2000 Collaborative Group, Lancet, 2004.
 The FDA recently approved a 23-mg formulation of donepezil
 Dose 5-10mg/day,
 Main S.E: GIT , insomnia, vivid dreams and night mares ( take after breakfast)

36. H Feldman, JAGS, 2003.

37. Rivastigmine
 Rivastigmine is a pseudo-irreversible
cholinesterase inhibitor that is selective
for acetylcholinesterase and
butyrylcholinesterase.
 The FDA recently approved a 13.3-
mg transdermal patch formulation
of rivastigmine,

38. Galantamine
 Galantamine is a reversible
competitive acetylcholinesterase
inhibitor with relatively less
butyrylcholinesterase inhibition
compared to rivastigmine.
 Competitive inhibitors potentially
are less active in brain areas that
have remaining high acetylcholine
levels and more active in other
areas.
 also functions as an allosteric
modulator of nicotinic receptors,
possibly enhancing cholinergic
transmission by presynaptic
nicotinic stimulation.
 Efficacy of galantamine has been
demonstrated at doses of 8 mg twice a
day and 16 mg twice a day, with fewer
adverse effects at the lower dose, in at
least four randomized trials of 3 and 6
months’ duration.

41. stopping of ChEI medication:
 unacceptable side effects
 lack of response to medication
 late stages of the disease
 Watch for return of insight leading
to depression and anxiety

42. MCI
 Many patients with mild cognitive impairment (MCI) are currently being treated with
cholinesterase inhibitors.
 Several studies have been conducted to evaluate the role of donepezil in delaying the
onset of AD inpatients with MCI.
 In a 3-year study in patients with amnestic MCI (aMCI), ,there was no delay in the onset
of AD in patients taking 10mg of donepezil compared with placebo.
 However, in APOε4 carriers, a significant delay in the conversion to AD was noted in
treated patients.
Nygaard HB. CLINICAL THERAPUTICS; 2013.

44. NMDA receptor antagonist
Memantine HCL
 Neuro-protective
 Glutamate is the principal excitatory amino acid neurotransmitter in cortical and
hippocampal neurons
 NMDA receptor is activated by glutamate
 important role in Learning and memory
 Excessive NMDA stimulation: excitotoxicity
 Agents that block pathologic stimulation of NMDA receptors may protect against
further damage ( selective for GluN2A, GluN2B subunits, which are expressed
predominantly in forebrain areas in adult tissue, particularly in the hippocampus,
cerebral cortex and thalamic regions.) Chaffey and Chazot, Current Anaesthesia &
Critical Care (2008)

45. Memantine HCL
 Most effective in moderate to severe
 Efficacy demonstrated in vascular
dementia
 No clear effect in LBD( Some reports
of worsening)

46. Memantine Change in Global and Cognition,
moderate - severe (Reisberg et al. Arch Neurol. 2006)

47. Memantine Discontinuation and the Health Status of
Nursing Home Residents With Alzheimer's Disease.
Fillit HM et al. J. of the American Medical Directors Association, JAMDA,2010

48. S.E
 Dizziness is the most common
side effect associated with
memantine.
 Confusion and hallucinations are
reported to occur at a low frequency
 Memantine use seems to increase
agitation and delusional behaviors in
some patients with AD.
 worsening of delusions and
hallucinations is particularly
problematic in patients who have
DLB

49. Combined ChEI and Memantine
 Treatment with memantine/ChEI combination therapy in
moderate-to-severe AD produces consistent benefits that appear to
increase over time, and that are beyond those of ChEI treatment
alone.
 Memantine plus donepezil resulted in significantly better
outcomes than placebo plus donepezil on measures of cognition,
activities of daily living (ADLs), global outcome, and behavior.

50. When to stop ttt?
 ABCDs of dementia medication, delaying decline in Activities of Daily Living, Behavior,
Cognition, and Delaying institutionalization.
 Our general practice is to continue patients on cognitive enhancers as long as at least
one of these goals remains, taking into account any issues with costs or adverse
effects.
 Behavior is often a goal of therapy, even in late-stage dementia and sometimes
withdrawing drugs such as a cholinesterase inhibitor or NMDA antagonist can unmask
or worsen behavioral problems.

51. Vitamin E and selegiline
 Alpha-tocopherol (vitamin E) and selegiline have been studied in AD because of
their antioxidant properties.
 The largest and most influential, but controversial, trial examining disease
progression in AD was the first Alzheimer's Disease Cooperative Study (ADCS)
that compared selegiline, alpha-tocopherol, or both with placebo.
 There was a delayed progression to outcome in the ADCS treatment groups
(placebo 440 days, selegiline 655 days, alpha-tocopherol 670 days, combined
treatment 585 days).
 A number of cognitive tests that were measured as secondary endpoints failed
to show any difference between the groups. Sano et al, NEJM, 1997.

53. Hormone replacement HRT
 Studies of estrogen and AD in postmenopausal women have focused on two areas:
* the role of estrogen in preventing the development of dementia; and
* the potential efficacy of estrogen in the treatment of dementia.
These investigations are based upon a large body of preclinical evidence that estrogen
enhances cerebral blood flow, prevents atrophy of cholinergic neurons, reduces
oxidative stress, and modulates the effects of nerve growth factors.
However, large randomized trials have now shown that the use of HRT with estrogen
plus progestin or estrogen alone in women aged 65 and older who are free from
dementia may increase the risk of developing dementia
www.Uptodate.com, 2011

54. STATINS
 Previous observations suggested lower risk of AD in those
taking “statins”
 Recently presented at 8th International Symposium on
Advances in AD therapy:
 Atrovostatin treatment associated with less decline in
memory, function, mood & behaviour in people with AD

55. Ginko Biloba
 A systematic review of ginkgo for cognitive
impairment and dementia concluded that ginkgo
biloba, while safe, has inconsistent and
unconvincing evidence of benefit.
 Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database
Syst Rev 2007

56. Vitamin B
 An 18-month randomized trial of high dose vitamin
B-complex supplementation (folate, B6, B12) in 340
patients with mild to moderate AD found no
beneficial effect on cognitive measures.
 Aisen PS, Schneider LS, Sano M, et al. JAMA 2008.

57. Omega 3 fatty acids
 Observational studies have suggested a possible
association between dietary intake of fish and
omega-3 fatty acids and a lower risk of dementia.
 However, clinical trials have not supported a
therapeutic role for omega-3 fatty acid
supplementation in the treatment of AD

58.  In recent years, insulin signaling has been characterized in postmortem brains from
AD patients .
 These studies report many deficiencies in insulin signaling, such as decreased insulin
receptor expression , insulin receptor substrate (IRS) expression, AKT activation.
 strong molecular evidence of deficient insulin signaling in AD patients.
 Because many of the proteins involved in insulin signal transmission are down
regulated or less active in AD, it is possible that increasing insulin levels in the brain
or increasing insulin sensitivity can help compensate for decreased signaling.

60. Non pharmacological treatment
Sensory enhancement or relaxation
• Massage/ touch
• Music
• White noise
• Aromatherapy
• Multisensory modalitied e.g. snoezelen
Social contact
• One- on- one interaction
• Pets
• Simulated interaction and family videos
Behavior therapy
• Stimulus control
• Differential reinforcement

61. Structured activities
• Arts
• Group exercises and singing
• Outdoor walk
Cognitive therapy
Staff training
Bright light therapy
Sleep intervention

62. Aromatherapy
 alternative medicine that uses
volatile plant materials, known as
essential oils, and other aromatic
compounds for the purpose of
altering a person's mind, mood,
cognitive function or health.
 Aerial diffusion
 Direct inhalation
 Topical applications
 Two basic mechanisms are offered
to explain the purported effects.
One is the influence of aroma on
the brain, especially the limbic
system through the olfactory
system.The other is the direct
pharmacological effects of the
essential oils.

63. Snoezelen
 controlled multisensory environment
(MSE)
 It consists of placing the person in a
soothing and stimulating
environment.
 These rooms are specially designed
to deliver stimuli to various senses,
using lighting effects, color, sounds,
music, scents, etc.
 The combination of different
materials on a wall may be explored
using tactile senses, and the floor
may be adjusted to stimulate the
sense of balance.
 50% reduction in distress and
stereotypical behavior, and
seventy-five percent less
aggression and self-injury

64. Pets

65. Interventional management
 Transcranial magnetic stimulation

66. rTMS-COG seems a promising effective and safe modality for AD treatment,
possibly as good as cholinesterase inhibitors.
ADAS-cog (average) improved by approximately 4 points after both 6 weeks and
4.5 months of treatment.
No side effects were recorded
Bentwich et al, J Neural Transm (2011)

67. FUTURE

69.  The transplantation of HB1.F3.ChAT cells in an AD animal model increases cognitive
function coinciding with up regulation of acetylcholine levels in the cerebrospinal
fluid. In addition, there is a large dispersion throughout the brain of the
transplanted stem cells which is important to repair the widespread cholinergic cell
loss in AD.
 Further studies are warranted to test the safety and effectiveness of these cells in
AD transgenic animal models

70. New drugs and new targets
 Recent advancements in AD research new strategies (Lane et al
2012):
 ■■ Anti-plaque strategies with monoclonal Ab (anti-Aß42 Ab:
oligomeric Aß 42 (for example, Solanezumab®, Crenezumab®).
(Passive immunization)
 Monoclonal Ab or gene therapy/strategy to target the Apoε4
variant.
 ■■ Target inflammatory pathways/mechanisms on the basis that
inflammatory role in pathogenesis of AD.

71. Passive
immunization
 Anti-plaque strategies with
monoclonal Ab (anti-Aß42
Ab: oligomeric Aß 42 (for
example, Solanezumab®,
Crenezumab®).

73. Active immunization
1st trial 2002 phase II
 289 patients
 18 developed meningioencephalitis,
generation of T cell response.
 20 showed reduction in AB plaque
load
2nd 2012 phase I
 CAD 106
 Generation of B cell response
 This small trial found CAD106 to be
safe and well tolerated,
 it generated an antibody response
to Aβ after 3 injections over 8
weeks.

75. Decreasing AB Production: γ and B
Secretase Inhibitors
semagacestat
 A recent Phase III trial
assessing the γ-secretase
inhibitor semagacestat
in patients with AD was
terminated early due to
clinical worsening and
other safety concerns.
avagacestat
 A Phase II trial in patients
with AD was recently
reported, with higher doses
again showing a trend
toward clinical worsening.
The avagacestat Program
was terminated by the drug
company in late 2012.

76. B secretase inhibitor
LY2886721
 Recently terminated a Phase II
study due to abnormal results on
liver function tests.
MK-8931
 A 7-day Phase I trial showed that
escalating doses were well
tolerated, and a large dose
dependent decrease in CSF Aβ of
up to 47% was seen, presumably by
lowering Aβ production.
 A phase II/III trial of MK8931 in
mild to moderate AD is now
enrolling patients

77. Blocking AB Signaling: Targeting Fyn
Kinase
Fyn kinase (Saracatinib)
 In the synaptic pathophysiology of
AD, with links to both Aβ and τ
pathology.
 Fyn is a member of intracellular
non receptor tyrosine kinases
 removal of Fyn kinase alleviates
synapse loss, and overexpression of
Fyn accelerates impairments in
spatial memory
cellular prion protein (PrPC)
 That acts as a high- affinity
receptor for toxic Aβ oligomers

78. Blocking τau -Mediated Toxicity: τ -
based Therapies
TRx0237
 A Phase II trial of TRx0237
compound,a modified version of
methylene blue thought to prevent
τ aggregation, is being conducted.
 Unpublished PhaseII results of an
earlier version of the drug* showed
that patients with moderate AD
given 60mg TID exhibited an
improvement of 5.5 points on the
ADAS-Cog at 24 weeks, where as
doses of 30 and100 mg had no
effect
 Remarkably, patients with both
mild and moderate AD receiving
this earlier version of the drug
were reported to have stable
clinical symptoms throughout a 50-
week period compared with
subjects receiving placebo

79. Souvenaids
 is a medical food product recently developed for use in AD.
 It contains a proprietary mix of nutrients that are precursors for phosphatides
essential for healthy neuronal function.
 After positive results in a Phase II trial in mild AD,in which treated patients saw
mild improvements in cognitive function over a 24-week period, a Phase III
study is expected.

80. IVIg
IVIg was found to contain antibodies against Aβ, a finding that represented the early
rationale for its use in AD. There was considerable excitement related to this therapy after
6 of 8 AD patients given IVIg experienced an improvement of 2.5 points on the MMSE after a
6-month treatment period.
In July2013, an 18-month, Phase III trial of IVIg was reported, enrolling 390 patients with
mild to moderate AD.
The study failed to meet the primary outcome measures of improved cognitive function
(ADAS-Cog) and improved measures of activities of daily living (ADCS-ADL).
Alzheimer’s association update, Sept, 2013

81. In light of these results, it is uncertain whether IVIg therapy
will be effective in mild to moderate AD, with a possible
exception for individuals carrying the APOε4 gene.
It remains to be seen whether IVIg has a role in the treatment
of individuals at risk for AD, either at a preclinical or MCI
stage.

83. Humanoid robot as a cognitive stimulation tool in
the therapy of dementia patients. Several software
modules have been programmed to generate the
robot behaviour in the therapy sessions.
Three types of robotherapy sessions have been
developed: physiotherapy, music and logic‐
language sessions.

85. “I am living
with dementia,
not dying with
dementia.”