This document discusses the treatment of dementia. It covers pharmacological and non-pharmacological management. For pharmacological management, there are three categories: symptomatic treatment of memory disturbance, disease-modifying treatments, and treatment of behavioral disturbances. Cholinesterase inhibitors are the mainstay of symptomatic treatment and include donepezil, rivastigmine, galantamine, and tacrine. Memantine is also used for moderate to severe cases. Non-pharmacological management includes cognitive training and behavioral therapies.

1. TREATMENT
OF
DEMENTIA

2. OUTLINE
 Definition and
Criteria
 Classification of
Dementia
 Staging of Dementia
 Classification
 Types and causes of
dementia
 Pathophysiology
Management of dementia
 PHARMACOLOGIC
MANAGEMENT OF
DEMENTIA
 Symptomatic
 Disease-modifying
treatments
 treatment of behavioral
disturbance
NON PHARMACOLOGIC
MANAGEMENT OF
DEMENTIA

3. Dementia
 Term dementia in Latin means “devoid of the
mind.”
 It is defined as an acquired deterioration in
cognitive abilities from a previously higher
level of functioning that impairs the
successful performance of activities of daily
living.
In 2010, there are 3.7 million Indians with dementia and
the total societal costs is about 14,700
crore(ALZHEIMER'S & RELATED DISORDERS SOCIETY OF
INDIA ARDSI 2010)

4. DSMD –SIMV -CIrVit eCrirai tfoerr Diaementia
Memory Impairment plus at least one of the
following
APHASIA (Deterioration of Language function)
APRAXIA (inability to Execute Motor function)
AGNOSIA
(inability to Recognise or Naming of Object)
Disturbance in executive functioning
with
• Impairment in occupational or social functioning
• Represent a decline from a previous higher level of
functioning

5. Mild cognitive impairment (MCI)
Original Criteria
 Memory complaint
preferably qualified by an
informant
 Memory impairment for
age
 Preserved general
cognitive function
 Intact activities of daily
living
 Not demented
By Peterson R, Negash S.
CNS Spectr. vol 13 2008
 Once the memory loss
becomes noticeable to the
patient and spouse and falls
1.5 standard deviations
below normal on
standardized memory
tests, the term MCI is
applied.
 approximately 50% of
patients with MCI
(roughly 12% per year)
will progress to AD over
4 years.
 10% of persons >70 and
20–40% of individuals
>85 have clinically
identifiable memory loss.
Harrison's 18 ed
> Chapter 371. Dementia

6. ROAD TO DEMENTIA

7. Staging of Dementias
 MILD: difficulties with checkbook maintenance,
complex meal preparations, complicated medication
schedules
 MODERATE: difficulties with simple food
preparation, household or yard work. May need some
assistance with self-care
 SEVERE: Need considerable assistance with
feeding, grooming and toileting
 PROFOUND: Largely oblivious to surroundings,
totally dependent
 TERMINAL: Bed bound; require constant care

8. Mini Mental State
Examiation :
Staging of Disease by
MMSE
Normal 27-30
Mild 25-26
Mild- Moderate 10-24
Moderate- Severe 6-9
Very Severe <6

9. MMSE

10. MMSE ‘norms’ by Age and
Educational Level
Educational level
AGE 0-4y 5-8y 9-12y >12y
18-24 23 28 29 30
35-39 23 27 29 30
50-54 22 27 29 30
70-74 21 26 28 29
80-84 19 25 26 28

11. Classification of Dementias
 Primary versus secondary based on the
pathophysiology leading to damaged brain tissue
 Cortical versus sub-cortical depending on
the cerebral location of the primary deficits
 Reversible versus irreversible depending on
treatment expectations
 Early (before age 65) versus late onset

12. Primary Degenerative Dementia:
•Alzheimer’s Disease
Causes of Dementia
•Fronto temporal dementia
 Parkinsons disease
 Huntington’s disease
•Dementia with Lewy Body
•Parkinsons disease
•Huntington’s disease
•Progressive supranuclear palsy
•Corticobasal degeneration
• ALS Parkinson's dementia complex of Guam
•Multisystem atrophy

13. Secondary Dementia:
VITAMIN
Deficiency
ENDOCRINE Chronic
Infections
Vit B12/Folic
acid
Hypothyroidism HIV
Thiamine B1 hyperthyroidism Neurosyphilis
Nicotinic acid
(pellagra)
Cushing Syndrome PML, Prion
Tuberculosis,
fungal, and
protozoal
Hypoparathyroidism Whipple's disease

14. Secondary Dementia
TOXIC Head
Trauma/diffuse
brain damage
Neoplastic
DIALYSIS
DEMENTIA
Aluminum
Chronic Subdural
Hematoma/Deme
ntia pugilistica
Primary Brain
Tumor
Drug
Poisoning
Alcoholism
Postencephalitis/
Postanoxia
Metastatic
brain tumors
Heavy metal
Poisoning
Mercury,lead
Normal Pressure
Hydrocephalus
Paraneoplasti
c limbic
encephalitis

15. Secondary Dementia
Miscellaneous Additional conditions in
children or adolescents
 Sarcoidosis
 Vasculitis
 CADASIL
 Acute intermittent
porphyria
 Recurrent
nonconvulsive
seizures
 Pantothenate kinase-associated
neurodegeneration
 Subacute sclerosing
panencephalitis
 Metabolic disorders (e.g.,
Wilson's and Leigh's
diseases, leukodystrophies,
lipid storage diseases,
mitochondrial mutations)

16. Overall Situation: USA DATA
Alzheimer’s
70 %
disease
Vascular
Dementia
15-20%
70% of dementia is Alzheimer’s
10-15% is Vascular dementia
10-15% Lewy Body dementias
5-10% Others
Lewy Body
Dementia
10-15 %
Others 5 %

17. Year : 2012 | Volume : 60 | Issue : 6 | Page : 618-624

18. Types
CORTICAL SUBCORTICAL MIXED
Alzheimer’s Parkinson’s Vascular Dementia
Frontotemporal
Dementia
Huntington’s
disease
Lewy body
dementia
CJD Normal pressure
hydrocaphalus
Neurosyphilis

19. REVERSIBLE (
DEMENTIA[10-20%]
IRREVERSIBLE
DEMENTIA[80-90%]
D= Drugs Alzheimer
E= Endocrine disorders Lewy Body dementia
M= Metabolic Frontotemporal Dementia
(Picks disease)
E= Emotional Parkinson disease
N= Nutritional Huntington’s disease
T = Toxic, Tumor, Trauma Creutzfeldt-Jakob disease
A= Alcohol others

20. BASELINE TESTS:
Baseline
investigations for
Dementia:
CBC, ESR S. Electrolytes
Calcium, Phosphate Syphilis
Chest X ray HIV
CT, MRI Thyroid Function test
B12, Folate Liver function tests
EEG, ECG Renal Function Tests

22. Pathophysiology of AD (Biochemical)
Cholinergic deficit
– progressive loss of cholinergic
neurones
– progressive decrease in
available ACh
– impairment in ADL, behaviour
and cognition
Hippocampus
Cortex
N. basalis Meynert

24. Alzeimer’s
Disease
Loss of
cholinergic
neurons
Senile plaques &
neurofibrillary
tangels
Glutamate
transmission
dysfunctiion
30%
symptoms
70%
Symptoms

25. Alzheimer’s Staging:

26. Management :Dementia
Reduce Cognitive
Symptoms
Reduce Behaviour
Symptoms
Slow disease progression
Delay the Onset of
Disease

28. PHARMACOLOGIC MANAGEMENT OF
DEMENTIA
 Three broad categories of dementia
pharmacotherapy:
Symptomatic treatment of memory
disturbance
Disease-modifying treatments
Symptomatic treatment of behavioral
disturbance

29. Symptomatic Treatment of AD
. The mainstay of symptomatic treatment of AD, so
far, is the cholinergic treatment strategies and
most widely used, till now, are the Cholinesterase
(ChE) inhibitors.
.
These agents
•Reduce the metabolism of acetylcholine
•Prolonging its action at cholinergic synapses.

30. Cholinesterase inhibitors:
two classes exist for the treatment of Dementia
Class Inhibit
Dual ChE inhibitors
– Rivastigmine Both AChE
– Tacrine and BuChE
Single ChE inhibitors
– Donepezil AChE
– Galantamine
Weinstock, 1999

31. FDA-approved drugs
Drug Target dose Approved for year
Tacrine 40 mg/day Mild to
moderate
1993
Donepezil 10 mg daily All stages 1996
Rivastigmine 6 mg twice
daily or 9.5-mg
patch daily
All stages 2000
Galantamine target dose 24
mg daily,
extended-release
Mild to
moderate
2001
Memantine 10 mg twice
daily
Moderate to
severe
2003

32. TACRINE
 In 1993 first Drug approved for the treatment
of Alzheimer's disease
 marketed under the trade name Cognex.
 Tacrine was first synthesised by Adrie Albert at
the University of Sydney.
 Tacrine is a centrally acting anticholinesterase and
indirect cholinergic agonist (parasympathomimetic).

33. Tacrine Pharmacokinetis
 Bioavailability 2.4–36% (oral)
 Protein binding 55%
 Metabolism Hepatic (CYP1A2)
 Half-life 2–4 hours
 Excretion Renal

34. Tacrine dose
Initiation of Treatment Dose Titration
 Cognex® is supplied as
capsules of tacrine
hydrochloride containing
10, 20, 30, and 40 mg of
tacrine.
 Cognex® brand of tacrine
hydrochloride is 40 mg/day
(10 mg QID).
 This dose should be
maintained for a minimum
of 4 weeks with every other
week monitoring of
transaminase levels
beginning 4 weeks after
initiation of treatment.
 Following 4 weeks dose to
be increased to 80 mg/day
(20 mg QID), providing
there LFT is normal
 Patients should be titrated
to higher doses (120 and
160 mg/day, in divided
doses on a QID schedule)
at 4-week intervals on the
basis of tolerance.

35. Tacrine Adverse Effects
Very Common >10% Common 1-10% incidence
 Increased LFTs
 Hepatitis
 Nausea
 Vomiting
 Diarrhea
 Headache
 Dizziness
 Indigestion,Belching
 Abdominal pain
 Myalgia
 Confusion
 Ataxia
 Insomnia
 Weight loss
 Constipation
 Somnolence
 Tremor
 Anxiety

36. Tacrine Overdose
 nausea, vomiting,
 salivation, sweating,
 bradycardia, hypotension, collapse,
 convulsions.
 Atropine is a popular treatment for overdose.

37.  Studies found that it may have a small beneficial
effect on cognition and other clinical measures
 though study data was limited and the clinical
relevance of these findings was unclear.
 Tacrine has been discontinued due to hepatotoxicity

38. DONEPEZIL
 In 1996, donepezil, a selective cholinesterase
inhibitor, was approved for use in Alzheimer disease.
 marketed under the trade name Aricept by its is a
centrally acting reversible acetylcholinesterase
inhibitor
 devoid of peripheral cholinomimetic adverse effects.

39. Pharmacokinetics
 Bioavailability 100 (%) not affected by the time of
day or food intake
 Protein binding 96%
 Half-life 70 hours
 peak plasma concentration is reached in 3 to 5 hours.
 It is extensively metabolized by the hepatic
isoenzymes CYP2D6 and CYP3A4.
 minimally affected by hepatic or renal disease and no
dose adjustment is necessary for these conditions.

40. Dosage
In mild to moderate A D Moderate to severe AD
 Disease, a starting dose
of 5 mg given once
daily should be used.
 a minimum of four to
six weeks, an increase
to 10 mg is
recommended.
 The usual dose is 5 to
10 mg once daily.
 indicates the same
regimen, but in a
minimum of three
months, a patient may
receive a dose of 23 mg
once daily.
 The maximum daily dose
is 23 mg once daily.
 In the UK, the maximum
licensed dose is 10 mg

41. DONEPEZIL
CONTRAINDICATIONS ADVERSE EFFECTS
 cardiac disease, cardiac
conduction disturbances,
chronic obstructive
pulmonary disease,
asthma, severe cardiac
arrhythmias and sick
sinus syndrome.
 gastrointestinal disorders
should use caution because
nausea or vomiting may occur.
 predisposition to seizures
should be treated with caution.
 Common side effects
include bradycardia
 cardiac conduction
disturbances
 nausea, diarrhea, anor
exiaabdominal pain
 vivid dreams and Several
cases of mania induced by
Donepezil have been
reported

42. Clinical Trials of Donepezil
 Study (Rogers et al 1996).
 Double-blind, placebo-controlled,
30-week,
parallel study involving
450 patients
with Alzheimer disease
 Results
 Significant improvement
on cognitive and clinical
global assessments.
Study (Rogers and Friedhoff
1996).
 Dose-ranging study on 161
patients with mild to
moderate Alzheimerdisease
who received donepezil 1,
3, or 5 mg, or placebo, daily
for 12 weeks
 Results
 Patients who received
donepezil 5 mg showed
significant improvement in
the Alzheimer Disease
Assessment Scale Cognitive
Subscale.

44. Clinical Trials of Donepezil
 Study (Doody et al 2009)
 A 48-week, randomized,
placebo-controlled trial of
donepezil for treatment of
patients with mild
cognitive impairment
 Results
 Donepezil produced small
but significant
improvement on the
primary measure of
cognition, but there was no
change on the primary
measure of global function
 Study (Farlow et al 2011).
 A pivotal phase 3 study of
the safety and tolerability
of increasing donepezil to
23 mg/d compared with
continuing 10 mg/d
 Results
 Good safety and tolerability
profile of donepezil 23
mg/d supports its favorable
risk/benefit ratio in
patients with moderate to
severe Alzheimer disease.

45. Rivastigmine (Rx) - Exelon
Mechanism of Action
PHARMACOKINETICS
 Reversible
acetylcholinesterase
inhibitor that causes an
increase in
concentrations of
acetylcholine, which in
turn enhances
cholinergic
neurotransmission
Absorption
 Bioavailability: 36% (PO)
 Duration: 10 hr (PO); 24 hr (patch)
 Peak plasma time: 1 hr (PO); 8 hr
(patch)
Distribution
 Protein bound: 40%
 Vd: 1.8-2.7 L/kg
Metabolism
 Metabolized by cholinesterase
Elimination
 Half-life: 1.5 hr (PO), 3 hr (patch)
 Total body clearance: 1.2-2.4 L/min
 Excretion: Urine (97%)

46. Rivastigmine - Adverse effects
common UNCOMMON
 Nausea (PO 47%; patch 21%)
 Vomiting (PO 31%; patch 6-
19%)
 Dizziness (PO 21%; patch 2-
7%)
 Diarrhea (PO 19%; patch 6-
10%)
 Headache (PO 17%; patch 3-
4%)
 Anorexia (PO 17%; patch 3-
9%)
 Abdominal pain (PO 13%;
patch 2-4%)
 Decreased weight (3-8%)
 Insomnia (PO 9%; patch
1-4%)
 Anxiety (PO 5%; patch
3%)
 Asthenia (PO 6%; patch
2-3%)
 Vertigo (2%)
 Fatigue (2%)

47. Rivastigmine Cautions
 Renal impairment
 Hepatic impairment
 Sick sinus syndrome
 Conduction abnormalities.
 H/O Asthma or COPD
 Pregnancy .

48. Transdermal Patch Technology:
Reservoir versus Matrix
Backing
Drug
Reservoir
Nitti VW, et al Urology. 2006;67:657–64
Backing
Drug + Polymer
+ Adhesive
Drug contained in adhesive layer along
with polymer
Smaller and thinner than reservoir patches
Reservoir
Matrix
Drug contained in separate layer,
with a rate-controlling membrane
Matrix Diffusion
Controlled Patch
Release Liner
Rate-Controlled
Reservoir/Membrane Patch
Dermal Layer
Release Liner Adhesive Layer

49. Exelon Transdermal
9.5 mg/24 h Patch

50. Where to Apply Exelon Patch
Apply to:
Upper and lower back
Upper arm
Chest
The skin should be clean,
dry and hairless before the
patch is applied
Normal daily activities,
such as bathing, are
permitted
1Lefèvre G, et al. J Clin Pharmacol
2007;47:471–8.

51. Exelon Transdermal Patch:
Smooth Continuous Delivery Through the Skin
Exelon 9.5 mg/24 h patch
Exelon 6 mg BID capsule
Plasma concentration (ng/mL)
25
20
15
10
5
0
0 6 12 18 24
Time (hours)
Exelon 9.5 mg/24 h patch delivered comparable average concentrations (AUC)
to those provided by an oral dose of 6 mg BID (12 mg/day)*
* Model-predicted analysis based on actual patient data corrected for body weight.

52. Starting transdermal ChEI therapy
Rivastigmine
4.6 mg/24 h
patch
Rivastigmine
9.5 mg/24 h
patch
One-step dose increase
4 weeks
Starting dose Target dose

54. Clinical trials Rivastigmine
 Study (Burns et al
2004)
 A retrospective analysis of
pooled data from 3
randomized, placebo-controlled,
double-blind, 6-
month trials involving 2126
patients with Alzheimer
disease suggests that
rivastigmine 6 to 12 mg/day
may benefit subjects with
more severe disease as well
as subjects with mild to
moderate impairment
 In an open-label,
comparative study of
rivastigmine with
donepezil and
galantamine, there were
no statistically significant
differences between the 3
drugs at 3 months
(Aguglia et al 2004).
 In a placebo-controlled
study, rivastigmine was
associated with moderate
improvements in
dementia associated with
Parkinson disease but also
with higher rates of
nausea, vomiting, and
tremor (Emre et al
2004).

55. Clinical trials Rivastigmine
 Results of a 6-month,
double-blind, randomized,
placebo-controlled study of a
transdermal patch in
Alzheimer disease
shows that the patch
provides efficacy
similar to the highest
doses of capsules with a
superior tolerability profile
and may offer convenience
important to many
caregivers and patients
(Winblad et al 2007).
 A retrospective analysis of a
large randomized, placebo-controlled
trial of Alzheimer
disease patients treated with
transdermal rivastigmine or
rivastigmine capsule compared
to placebo showed greatest
treatment effects in patients
with more advanced dementia
who received rivastigmine, and
these were considered to be
most likely due to greater
decline in the patients treated
with placebo (Farlow et al
2011).

56. Galantamine (Nivalin, Razadyne, Razadyne
ER, Reminyl, Lycoremine)
 It is an alkaloid that is
obtained synthetically
or from the bulbs and
flowers of Galanthus
caucasicus
(Caucasian snowdrop)
 Galantamine
hydrobromide was
approved in 2001 by the
FDA Indicated for the
treatment of mild to
moderate dementia IN
Alzheimer's.

57. Galantamine-MOA
 weak competitive
and reversible choline
sterase inhibitor in all
areas of the body.
 It increases the
concentration and
thereby action
of acetylcholine in
certain parts of the brain.
 It has shown activity in
modulating the nicotinic
cholinergic receptors on
cholinergic neurons to
increase acetylcholine
release.

58. Pharmacokinetics
Galantamine
DOSAGE
 Bioavailability - 80 to
100%
 Protein binding- 18%
 Metabolism-Hepatic
 Half-life-7 hours
 Excretion -
Renal (95%, of which
32% unchanged), fecal
(5%)
 in twice-a-day tablets, in
once-a-day extended-release
capsules, and in
oral solution.
 The tablets come in
4 mg, 8 mg, and 12 mg
forms.
 The capsules come in
8 mg, 16 mg, and 24 mg
forms.

59. Clinical Trials with Galantamine
Study (Raskind et al 2004).
 Patients with mild-to-moderate
Alzheimer disease
who had been randomized to
galantamine therapy in
previous trials received open-label
continuous galantamine
therapy for up to 36
months(Raskind et al 2004).
Results
 Cognitive decline over 36
months with continuous
galantamine treatment was
substantially less than the
predicted cognitive decline of
untreated patients.
Study (Suh et al 2004)
 Prospective, randomized
multicenter, double-blind
study of patients with mild-to-
moderate Alzheimer
disease: dose 8 mg/day, 16
mg/day, or 24 mg/day ).
Results
 All dose schedules were well
tolerated with significant
improvements in all 3
treatment groups.

60. Galantamine-Adverse effects
common Rare
 Nausea, vomiting,Diarrhea,
abdominal pain, upper
abdominal pain, dyspepsia,
stomach discomfort, abdominal
discomfort
 Bradycardia,First degree
atrioventricular block,
palpitations, sinus bradycardia,
supraventricular extrasystoles,
flushing, hypotension
 Dizziness, headache, tremor,
syncope, lethargy, somnolence
 Blurred vision
 confusion
 decreased urination
 dizziness, faintness, or
lightheadedness
 dry mouth
 fainting
 fast, irregular, pounding, or racing
heartbeat or pulse
 feeling of warmth
 rapid breathing
 redness of the face, neck, arms, and
occasionally, upper chest
 sunken eyes,sweating, thirst

61. Memantine
 Memantine is the first in a novel class
of Alzheimer's disease medications acting on
the glutamatergic system by blocking NMDA
receptor.
 Memantine is approved by the U.S. F.D.A and the
European Medicines Agency for treatment of
moderate-to-severe Alzheimer's disease

62. Memantine
Pharmacokinetic MOA
 Bioavailability~100%
 Metabolism-
Hepatic (<10%)
 Half-life- 60–100
hours
 Excretion - Renal
 Memantine is a low-affinity
voltage
dependent uncompetitive
antagonist at
glutamatergic NMDA
receptors
 non-competitive antagonist
at the 5-HT3 receptor, this
serotonergic activity in the
treatment of Alzheimer's
disease is unknown.

64. Memantine -Adverse effects
Common Less common
 confusion, dizziness,
drowsiness,
 headache, insomnia,
agitation
 hallucinations.
 vomiting, anxiety,
 hypertonia
 cystitis,
 increased libido
rare
 extrapyramidal side
effects(such as dystonic
reactions etc.) may
occur, in particular, in
the younger population

65. Clinical trials Memantine
The M-Best Study
 The M-Best Study (Benefit and
Efficacy in Severely demented
patients during treatment with
memantine) was a double-blind,
placebo-controlled,
phase III trial of memantine
conducted in Sweden on care-dependent
patients with severe
dementia (Winblad and Poritis
1999).
 The trial population consisted of
161 patients, 51% with
vascular dementia and 49%
with Alzheimer disease.
Treated patients were given 10 mg
memantine per day for 12 weeks,
and evaluation was done using
 Clinical Global Impression
of Change by the physician
and Behavioral Rating Scale
for Geriatric Patients by the
nursing staff.
 The results supported the
hypothesis that
memantine treatment
leads to functional
improvement and
reduces care
dependence in severely
demented patients.

66. The DOMINO-AD clinical trial
 This study looked at 295 people
with moderate to severe Alzheimer's
disease
 All of the study participants had been
prescribed donepezil for at least three
months, and had been taking a dose of
10mg for at least the six weeks prior to
the trial. The trial lasted for 52 weeks.
 Participants were divided into
four different groups and were
each given two drugs. These
groups were:
 donepezil and memantine
 donepezil and placebo memantine
 placebo donepezil and memantine
 placebo donepezil and placebo
memantine
 Standardised Mini-
Mental State
Exam (SMMSE) and
their abilities in daily
life using the Bristol
Activities of Daily
Living Scale (BADLS).
 All of these measures
were taken at the start
of the study, after six
weeks, at 18 weeks, at
30 weeks and finally
after 52 weeks.

67. The DOMINO-AD clinical trial
RESULTS
 There were benefits to cognitive function of taking donepezil (about
32% less cognitive decline than those on placebo).
 Memantine also showed these benefits, although smaller (about
20% less decline than those on placebo).
 Compared to placebo, memantine led to fewer behavioural
symptoms developing, showing about 83% fewer symptoms.
 The functional benefits of continuing donepezil showed about 23%
less deterioration than those on placebo.
 The functional benefits of memantine were about 11% less
deterioration than those on placebo.
 There were also small reductions in caregivers' psychological
symptoms with either of the drugs, although these were not large
enough to be measured reliably with statistics.
 Combined treatment with both donepezil and memantine
was not better than treatment with donepezil alone for
any of the measures.

68. RCT of donepezil &/or memantine &/or
placebo in patients with moderately
severe/severe AD (MMSE 5-13) who have
been on donepezil for at least 12 months
Howard et al 2012

69. RESULTS
DELAY OF
PROGRESSION:
Duration
Memantine alone 2-3 years
Memantine + Ch E
5-6 years
inhibitors
Ch E Inhibitors alone 1.5 years

71. TREATMENT OPTIONS IN DEMENTIA
AD VaD FTD LBD
DONEPEZIL ChE Inhibitors No ChE
inhibitors
ChE
inhibitors
RIVASTIGMIE HMG CoA SSRI SSRI
GALANTAMINE Stroke Prevent Antipsychotics Memantine
MEMANTINE Memantine Memantine Levodopa
SSRI Antipsychotic Avoid
Antipsychot
ics

72. Disease-Modifying Agents
Proposed or unregulated drugs which
require further studies
Selegeline
Vit-E
Oestrogen
Prednisolone
NSAIDs
Ginkgo biloba
Statins
IVIg
Glycogen syntehtase
kinase 3 (GSK 3)
β-secretase
inhibitors
γ-secretase
inhibitors
α-secretase
enhancers
Immunotherapy

73. Disease-Modifying Agents
 Vitamin E
 Limits free-radical formation, oxidative stress and lipid
peroxidation
 Promotes survival of cultured neurons exposed to
beta amyloid
 Clinical trials have not be overwhelmingly convincing
 Selegiline
 MAO-B inhibitor, increases brain catecholamines
 Also has antioxidant properties
 Clinical trials – alone and in combination with Vit. E not
effective

74. Disease-Modifying Agents
 Anti-Inflammatory drugs
 Pathophysiological studies demonstrate a marked
inflammatory reaction induced by amyloid with microglial
activation and cytokine release
 Case-control studies of subjects taking NSAIDs regularly
for arthritis demonstrate a reduced odds-ratio for
developing AD
 Recently developed NSAIDS currently in clinical trials of
AD
 Estrogen
 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

75. Disease-Modifying Agents
 Statins
 Direct association between amyloid processing and
cholesterol in the brain
 An indirect effect via decreasing the risk of stroke, since
even small vascular lesions worsen the severity of
Alzheimer's disease
 Ginkgo Biloba
 A single placebo-controlled trial with an extract of ginkgo
biloba showed a very modest improvement on cognitive
testing
 Only 50 percent of the treatment group completed the trial
 Use of ginkgo not recommended due to limited efficacy and
lack of regulation, including variability in the dosing and
contents of herbal extracts

76. Disease-Modifying Agents
 Idebenone
 Synthetic analogue to Co-Q10, known to have anti-oxidant
properties
 Controlled clinical trials have shown modest improvement
in cognitive function with highest doses
 Side effects including liver enzyme abnormalities (non-serious)
along with predominant G-I upset
 Negative trials
 Propentofylline (stimulates synthesis and release of NGF)
 Acetyl-L-carnitine (promotes ACh release, increases
acetyltransferase activity, has antioxidant properties)

77. The amyloid cascade hypothesis & drugs in
clinical trials
Statins - promotes
alpha secretase
Flurizan - modulates
gamma secretase
Lilly - inhibits gamma
secretase
Alzhemed - anti-fibrillar
Active and passive
immunisation ?
Adapted from Biochem. Soc. Trans. (2005) 33, 553-558

78. Active and passive beta amyloid immunisation
against AD
 Vaccination against Aβ42
has proved highly efficacious in
mouse models of AD, helping
clear brain amyloid and
preventing further amyloid
accumulation.
 In human trials, this approach
led to life-threatening
complications, including
meningoencephalitis
 modifications of the vaccine
approach using passive
immunization with
monoclonal antibodies are
currently being evaluated in
phase 3 trials.

79. Bapineuzumab (anti-amyloid antibody)

80. Bapineuzumab (anti-amyloid antibody)
“I think the data are pretty clear from this trial that
bapineuzumab is not effective for mild to
moderate dementia, and the company was wise to
stop the ongoing trials in that population,” said
Salloway, who leads one of the trial sites.
Another antibody (solanezumab) also showed
cognitive & functional benefit in mild AD.results
awaited

81. Behavioral Problems in AD
 depression (occurs in 20-40% - esp. AD and
VaD)
 psychosis (occurs in 30- 50%) - usually see
paranoid delusions (theft, infidelity)
 wandering/purposeless activity
 agitation/threatening behavior
 sleep disturbances
 delirium - minor insults can lead to major
decompensations

82. Depression and Alzheimer’s
 Common early in the course of the illness
 Incidence 40-50%
 Use SSRIs first; avoid anticholinergic
antidepressants
 ECT can be helpful but may temporarily worsen
cognitive symptoms

83. Treatment of Depression
 Recognize that irritability and/or apathy
/withdrawal may be indicative of depression
 Allow patient choices and control
 Identify pleasurable activities (such as singing old
songs, pet therapy, etc.)
 Cognitive enhancers (e.g. Aricept) may help

84. Agitation
 Non-aggressive
 verbal: complaining, constant requests for
attention, repetition of words, constant talk,
screaming
 physical: pacing, disrobing, stereotypies, trying to
get to a different place
 Aggressive
 Verbal: threats, name calling, obscenities
 Non-verbal: biting, scratching, spitting, kicking,
pushing, swinging fists

85. Medications for Agitation
 Buspirone – Takes a while to work
 Antidepressants (SSRIs, Trazodone)
 Anticonvulsants (esp. valproate)
 Atypical Antipsychotics (stroke risk concerning)
 Low dose narcotics?
 Estrogen?

86. Treatment of Psychosis
 Traditional antipsychotics
 Low potency (chlorpromazine)– orthostasis, sedation,
anticholinergic
 High potency (haloperidol)– EPS/TD but otherwise well
tolerated
 New generations drugs (e.g. olanzapine, quetiapine,
risperidone)- less EPS/TD but still see anticholinergic, BP
and sedative effects

87. Treatment of Insomnia
 Sleep hygiene (avoid caffeine, etc.)
 Treat causative psychiatric or medical disorders
 Phsysiological remedies - melatonin, warm milk,
lavendar oil
 Medications - Benadryl, benzos, sedating
antidepressants or antipsychotics (all these drugs can
make memory and confusion worse)
 Light Therapy - to reset natural circadian rhythms
for sleep

88. Use of Atypical Antipsychotics
 Older, “typical” agents such as haloperidol and
thioridazine (mellaril) associated with significant
extrapyramidal symptoms
 Theoretically combination of dopamine and
serotonin effects of atypical agents allow treatment
of positive and negative psychotic symptoms with
less EPS

89. Risperidone
 Evidence demonstrates efficacy in treatment of psychotic
and behavior symptoms in patients with dementia
 Exacerbates movement disorder in patients with
Parkinson’s
 Start .25/day, average daily dose 1-1.5mg/day
 EPS in dose dependent manner (6mg/day)
 Insomnia, hypotension, weight gain
 Elevation of prolactin levels

90. Olanzapine
 Evidence that it is effective in AD patients
 Increases motor symptoms in PD patients
 Recommended not to use with PD
 Start: 1.25-2.5/day, increase to 5/day (dosages of 10-15/day
are not more effective!)
 More sedating than others (more anticholinergic effects)
 Sedation, weight gain, orthostatic hypotension, seizures,
glucose intolerance

91. Quetiapine
 Showing promise in patients with AD and PD
 Does not exacerbate movement disorder of PD
 May be first line for PD patients with psychosis
 12.5 QHS, titrate every 3-5 days
 Sedation, HA, orthostatic hypotension
 ?Cataract formation

92. Ziprasidone
 New, clinical data lacking
 Non dose-dependent QT prolongation

93. Clozapine
 Very effective in treating psychosis in PD patients
 The most effective agent in treatment of drug
induced psychosis in PD
 Some efficacy with AD patients
 Start: 6.5mg/day
 Agranulocytosis, frequent monitoring limits use

94. Caregiver Burden
 Alzheimer’s caregivers spend an average of 69 to
100 hours per week providing care
 Caregivers of patients suffering from
dementia(compared to control subjects) reported:
 46% more physician visits
 Over 70% more prescribed drugs
 More likely to be hospitalized
 More than 50% of caregivers are at risk for clinical
depression

95. Behavioral Strategy
 Scheduled toileting,
prompted voiding
for incontinence.
 Graded assistance, &
positive
reinforcement to
increase functional
independence
 Music, esp. during
meals, bathing
Walking , Light
Exercise

96. Other Drugs in the Pipeline
 Tau protein modulators (to prevent abnormal
phosphorylated ‘tau’ protein
 Bryostatin – drug that stimulates brain protein
production. Reduces B-amyloid levels in mice,
enhances memory and learning.
 New generation NSAIDS (flubiprofen) – testing
in humans looks promising
 Immune enhancers (immunoglobulin)
 New vaccines and new anticholinesterases
(huperzine A)
 LADOSTIGIL-multimodal drug

97. Dementia and clinical trials
Where next?
 Disease modifying drugs need to start early
 Much of the damage been done by the time the patient presents
with dementia
 We need to consider new targets
 Is amyloid the cause, or just a byproduct? What about tau? What
about inflammation?
 We need to have better outcome measures
 Current assessments do not always reflect outcomes that matter to
patients and families.
 We need more patients to enter clinical trials
 Recruitment into dementia clinical trials is a fraction of the number
entering cancer trials

98. Take Home Points
 Cholinesterase Inhibitors are MODESTLY
effective in treatment of mild to moderate AD
 Cholinesterase Inhibitors are probably
effective in more severe AD
 No large difference in efficacy between
agents, but Donepezil more easily titrated
and tolerated
 Evidence to support use of cholinesterase
inhibitors for vascular and vascular/AD dementia
 Memantine looks to be effective for more
severe AD and vascular dementia, will
likely be used in combination with cholinesterase
inhibitors