SlideShare una empresa de Scribd logo
1 de 123
Descargar para leer sin conexión
ETIOPATHOGENESIS
MANAGEMENT AND RECENT
ADVANCES IN ALZHEIMERS
DISEASE
Presented by Dr. Karrar Husain
Moderator – Dr. M. Amir Usmani
1
2
 INTRODUCTION AND HISTORY
 EPIDEMIOLOGY
 ETIOPATHOGENESIS
 ASSESMENT
 DIAGNOSIS AND D/D
 MANAGEMENT
 PREVENTION
INTRODUCTION
HISTORY
3
INTRODUCTION
 Alzheimer’s disease (AD) is the commonest progressive,
dementing neurodegenerative disease in elderly, which
affects innumerable people each year, and these numbers are
likely to further increase as the population ages.
 In addition to the financial burden of AD on health care
system, the disease has powerful emotional impact on
caregivers and families of those afflicted.
4
BRIEF HISTORY
 Alois Alzheimer, a German physician,
is credited with being the first to
describe AD.
 In 1906, Dr. Alzheimer observed a
patient, Auguste Deter, in a local
asylum who exhibited strange
behaviors. He followed her care and
noted her memory loss, language
difficulty and confusion. Alois Alzheimer
5
 After her death at the age of 51, he examined her brain
tissue. The slides showed what are now known as plaques
and tangles.
 In 1911, Doctors were using Dr. Alzheimer’s research to base
diagnosis.
 In the 1960’s British pathologists determined that AD was not
a rare disease of the young but rather what had been termed
“senility.”
 In the 1990’s researchers identified that the beta amyloid
protein was a factor in AD.
6
7
EPIDEMIOLOGY
RISK FACTORS
PROTECTIVE FACTORS
8
 MC cause of dementia, > 65yr.
 Starting with 0.5% prevalence at 55 yrs., it goes on doubling
every five years (60yrs-1%; 65yrs. – 2%; 70 yrs. -4%; 75yrs.-8%
and so on)
 Risk at the age of 80 years is around 15 to 20%
 About 7.7 million new cases of dementia each year. A new
case detected in every 4 seconds somewhere in world.
EPIDEMIOLOGY
WHO
9
 The incidence rates per 1000 person-years for AD
was
 11.67 for ≥55 years
 15.54 for aged ≥65 years.
Neurol India. 2012 Nov-Dec;60(6):625-30. doi: 10.4103/0028-3886.105198.
10
COMMON TYPES OF DEMENTIAS
Type of Dementia % in total Cases
Alzheimer’s Dementia 50-55
Vascular Dementia 30-35
Lewy body Dementia 5-7
Pick’s Dementia 3-5
Other Dementias 10-15
11
Ziegler-Graham K et al. Alzheimer’s & Dememtia 2007;3(Suppl):S168–9
New Estimate of Dementia Worldwide
12
ALZHEIMER’S PREVALENCE
Qui et al. (2009). Dialogues in Clinical Neuroscience, 11(2), 111-128.
13
14
RISK FACTORS
 Age : every 5 yr beyond 65, the % of people with AD doubles
 Family history : strong genetic component
1. Early onset – fully penetrant
2. Late onset – reduced penetrant
 Gender – women, ? Estrogen
 Tobacco
 Head injury
15
 Obesity
 Hypertension , diabetes
 Elevated serum cholesterol
 Elevated serum homocysteine
 Depression
 Lack of intellectual stimulation/education
16
PROTECTIVE FACTORS
 Physical activity
 Caffeine consumption
 Antioxidants – VITAMIN C, E, B6 and B12
 Folate
 N -3 fatty acid intake
 Speaking > 2 language
17
PATHO PHYSIOLOGY
GENETICS
18
 AD is characterized by generalized cerebral cortical atrophy,
neuronal loss, widespread cortical neuritic plaques and
neurofibrillary tangles.
 Following mechanisms have been attributed for the
development of Alzheimer’s dementia
 Amyloid cascade theory
 Neuronal loss
 Cholinergic hypothesis
 Excitotoxicity
 Genetic factors
PATHOGENESIS AND PATHOPHYSIOLOGY
19
 Alzheimer’s disease begins with the abnormal build-up of an
amyloid protein in the brain from APP(amyloid precursor
protein).
 APP normally found in the cell membranes of neurons and
normally metabolised by a protease enzyme α–secretase.
 In AD, the metabolism of APP is altered by two other enzymes β
and γ secretase and is called β amyloid (Aβ).
AMYLOID CASCADE THEORY
20
 Amyloid-β is originated by the alternative cleavage of the
amyloid precursor protein (APP) into smaller peptides (Aβ1-
40 and Aβ1-42) by two other enzymes β and γ secretase
 Aβ1-42 is more prone to form insoluble aggregates (and
therefore more toxic) than Aβ1-40.
 Once Aβ is formed, it accumulates into insoluble sheets
(called β-pleated sheets).
21
 The interaction between genetic and environmental factors,
along with the homeostatic changes that pertain to the
ageing, seems to affect the balance between production and
clearance of toxic Aβ peptides.
 These deposits are neurotoxic and activate inflammatory
reaction resulting in the formation of senile or neuritic plaque.
 This is accompanied by hyperphosphorylation of tau protein,
supporting the microtubules.
22
 Hyperphosphorylated Tau aggregates into oligomers to form
NFTs.
 Several protein kinases are involved in this process, namely
glycogen synthase kinase-3 beta (GSK3β), cyclin-dependent
kinase-5 (CDK5), and extracellular signal-related kinase-2
(ERK2).
 GSK-3β, the most important Tau kinase in neurons, is
overactive in AD
23
Journal of Alzheimer’s Disease 33 (2013) S185 -S194
DOI 10.3233/JAD-2012-129028
24
25
 The classic gross neuro-
anatomical observation is
 Diffuse atrophy with
widening cortical sulci
 Enlarged cerebral
ventricles.
 There is a progressive
loss of neurons and their
supportive glial cells.
 The loss is more marked
in the entorhinal cortex,
hippocampus and basal
forebrain.
NEURONAL LOSS
26
Source: Image from the Alzheimer’s Society of Saskatchewan with permission from Alzheimer’s Broken Brain.
Alzheimer’s Brain Normal Brain
27
28
 Levels of acetylcholine, noradrenaline, serotonin, γ-
aminobutyric acid (GABA), glutamate, somatostatin,
neuropeptide Y, and substance P have all been documented
to be reduced in the brains of AD patients.
 Reductions in acetylcholine and choline acetyltransferase are
the most profound.
 Neuronal loss in the basal forebrain, which is the major
region from which cholinergic projections originate.
CHOLINERGIC HYPOTHESIS
29
 Excessive release of glutamate into the synapses.
 Excessive influx of calcium into the cells leading to cell death
called excitotoxicity.
 Also lead to excessive production of Aβ and tau
phosphorylation.
EXCITOTOXICITY
30
 Growing evidence for the role of additional factors such as
oxidative stress, neuroinflammation, and mitochondrial
dysfunction in the pathogenesis of AD.
31
GENETICS
 Four genes
1. Presenelin 1- chr 14
2. Presenelin 2- chr 1
3. Amyloid beta protein precursor- chr 21
4. Apolipoprotien E gene – chr 19
 Typically divided into – early onset and late onset
Arch. Neurol. 1998;55:294-296
32
GENETICS OF EARLY ONSET
 APP gene
 Increase the production of amyloid.
 Age of onset range from – 39 to 68 yrs
 6 different mutation – all are fully penetrant.
 APOE-4 mutation further decrease the age of onset.
Arch. Neurol. 1998;55:294-296
33
 THE PRESENELIN GENES
 Half of the early onset AD patient
 Increase the production of amyloid and promote apoptosis.
 It increase the production of Aß 1 -42,which is more
hydrophobic more prone to agreggation, hence more toxic
 All PS1 mutation are fully penetrant and autosomal dominant
 Age of onset in PS1 mutation range from 32 to 56 yrs
 Age of onset in PS2 mutation range from 40 – 85 yrs
Arch. Neurol. 1998;55:294-296
34
GENETICS OF LATE ONSET AD
 APOE GENE
 Has 3 alleles – 2,3 and 4…. 4 is associated with pathology
 Normal gene promote proteolysis and clearence of amyloid,
and mutant gene promote aggregation and deposition of
amyloid.
 Increase the risk of disease.
 Age of onset 60s
 It decrease the age of onset with APP mutation.
Arch. Neurol. 1998;55:294-296
35
36
SIGN AND SYMPTOMS
ASSESMENT
LABORATORY
IMAGING
37
SIGN AND SYMPTOMS OF AD
38
Who should be evaluated for AD
 Age more than 60yr
 People with risk factors – head injury, CV risks
 People with memory or cognitive complaints, with or without
change in functioning.
 Memory difficulty noted by friends, relatives or spouse.
 Patient with depression or anxiety without memory
complaints
39
ASSESMENT
 History
1. Patient
2. Relatives
 Comprehensive physical and neurological examination
 Cognitive evaluation
 Functioning status
 Lab work
 Imaging
40
HISTORY
 Memory impairment – trouble remembering recent
conversation, events, appointments, frequently misplaces
objects.
 Executive impairment – deterioration of complex task
performance, decreased ability to solve problems, impaired
driving.
 DRUGS
 Focal motor or sensory symptoms
 Behavior personality and mood changes
41
TOOLS
Screening
 Mini Mental State Examination (MMSE) (Folstein et al. 1975)
 Hindi Mental State Examination (HMSE) (Ganguli et al. 1995)
 Hindi Cognitive Screening Test (Tiwari and Tripathi, 2011)
 St. Louis University Mental State (SLUMS) Exm. (JE Morley,
2000)
 Clock Drawing Test (CDT) (Shulman et al. 1993)
 Bender Gestalt Test (BGT) (Lauretta Bender, 1938)
 Hachinski Ischemic Scale (1975)
42
Detailed Assessment
 Survey Psychiatric Assessment Schedule (Bond et al. 1980)
 CAMDEX-R (Roth et al. 1986, 1998-R)
 Alzheimer's Disease Assessment Scale (Rosen et al. 1984)
 Schedule for Clinical Assessment in Neuropsychiatry (SCAN)
(WHO, 1996)
 Clinical Dementia Rating (Morris, 1993)
 Blessed Dementia Scale (Blessed, 1968)
43
Scoring:
0- 4: Severe,
5-14: Mod.
15-19: Mild
Dementia;
20-24: MCI,
25-28 :Age
related Cog
Impairment,
29-30:Normal
44
45
46
Features Score
1. Abrupt 2
2. Stepwise deterioration 1
3. Fluctuating course 2
4. Nocturnal confusion 1
5. Relative preservation of
personality
1
6. Depression 1
7. Somatic Complaints 1
8. Emotional incontinence 1
Features Score
9. History or presence of
hypertension
1
10. History of strokes 2
11. Evidence of associated
atherosclerosis
1
12. Focal neurologic symptoms 2
13. Focal neurologic sign 2
Total Score 18
Hachinski Ischemic Scale (1975)
Scoring
0-4: Alzheimer's Dementia;
5-6: diagnosis unclear;
7 or more : Vascular Dementia
47
48
Score Error(s)
1 No error
2 Minor visuospatial error
3 Inaccurate
representation of “10
past 11”
4 Moderate visuospatial
disorganization of
times
5 Several disorganization
6 No reasonable
representation of a
clockScore≥ 3: Cognitive deficit
CLOCK DRAWING TEST
FUNCTIONAL STATUS
49
50
LABORATORY EAVALUATION
 CBC, full chemistry, TSH.
 Serum B12 and folic acid
 No value of genetic testing at present
 CSF markers – used only for research purpose not
recommended for clinical diagnosis
• Amyloid beta 42 - low
• Total tau - elevated
• Phosphorylated tau - elevated
51
 CSF marker may assist in differentiating from other dementia.
 A study in 2014 recommended the ratio of tau to A beta 42
with a cut of point of > 0.52 for differentiating AD from other
dementia…its more sensitive than individual marker.
 Its also important in predicting progression of MCI and
dementia.
F.H. Duits et al. / Alzheimer’s & Dementia -(2014) 1–11
52
F.H. Duits et al. / Alzheimer’s & Dementia -(2014) 1–11
53
IMAGING
 STRUCTURAL IMAGING – CT, MRI
 May reveal atrophy, white matter changes
 Not sensitive/specific to AD.
 In AD – diffuse cerebral atrophy, enlarged sulci, increased
size of ventricles, loss of hippocampal volume.
54
CEREBRAL ATROPHY
55
 FDG - PET
 Functional imaging of brain metabolism.
 It measures synaptic activity in different part of brain
 In AD – temporal and parietal glucose hypometabolism.
 Can differentiate AD from FTD.
 IOFLUPANE
 SPECT for evaluation of presynaptic dopamine
transporters, useful in differentiating AD from lewy body
dementia
56
57
AMYLOID IMAGING
 11C – labelled pittsburgh compound B
 First PET ligand to visualise beta amyloid in living patient
 It have short half life.
 Flourine 18 agents have longer half life and FDA
approved.
 Sensitivity – 80 to 93%
 Specificity – 91 to 96%
58
59
PET TAU IMAGING
 In vivo marker of abnormally phosphorylated TAU
protein.
 Tangles correlate best with cognitive impairment
 Amyloid may be present for years in the absence of
impairment
 Combined amyloid and TAU imaging my help in early
diagnosis and intervention.
60
Alzheimer’s & Dementia 7 (2011) 257–262
61
Alzheimer’s & Dementia 7 (2011) 257–262
62
THANK YOU
63
64
ETIOPATHOGENESIS
MANAGEMENT AND RECENT
ADVANCES IN ALZHEIMERS
DISEASE
Presented by Dr. Karrar Husain
Moderator – Dr. M. Amir Usmani
65
66
 INTRODUCTION AND HISTORY
 EPIDEMIOLOGY
 ETIOPATHOGENESIS
 ASSESMENT
 DIAGNOSIS AND D/D
 MANAGEMENT
 PREVENTION
DIAGNOSTIC CRITERIA
DIFFERENTIAL DIAGNOSIS
67
DSM 5
68
 NEUROCOGNITIVE DIORDERS
 DELIRIUM
 MAJOR NEUROCOGNITIVE DISORDERS
 MILD NEUROCOGNITIVE DISORDERS
Mild NCD
69
A. Evidence of modest cognitive decline from a previous
level of performance in one or more cognitive
domains based on:
1. Concern of the individual, a knowledgeable informant, or
the clinician that there has been a mild decline in
cognitive function; and
2. A modest impairment in cognitive performance,
preferably documented by standardized
neuropsychological testing or, in its absence, another
quantified clinical assessment.
B. The cognitive deficits do not interfere with capacity
for independence in everyday activities
70
C. The cognitive deficits do not occur exclusively in
the context of delirium.
D. The cognitive deficits are not better explained by
another mental disorder.
 Specify:
 Without behavioral disturbance
 With behavioral disturbance
71
 Specify whether due to
 Alzheimer’s disease
 FTD
 LBD
 Vascular
 TBI
 Substance/medication use
 ………
 Unspecified
Major NCD
72
A. Evidence of significant cognitive decline from a
previous level of performance in one or more
cognitive domains based on:
1. Concern of the individual, a knowledgeable informant, or
the clinician that there has been a significant decline in
cognitive function; and
2. A substantial impairment in cognitive performance,
preferably documented by standardized
neuropsychological testing or, in its absence, another
quantified clinical assessment.
B. The cognitive deficits interfere with independence in
everyday activities.
73
C. The cognitive deficits do not occur exclusively in
the context of delirium.
D. The cognitive deficits are not better explained by
another mental disorder.
 Specify:
 Without behavioral disturbance
 With behavioral disturbance
74
 Specify whether due to
 Alzheimer’s disease
 FTD
 LBD
 Vascular
 TBI
 Substance/medication use
 ………
 Unspecified
75
 Specify current severity
 Mild
 Moderate
 Severe
Major or Mild NCD Due to Alzheimer’s
76
A. The criteria are met for major or mild
neurocognitive disorder.
B. There is insidious onset and gradual progression
of impairment in one or more cognitive domains.
C. Criteria are met for either probable or possible
Alzheimer’s disease as follows:
 For major neurocognitive disorder
 For mild neurocognitive disorder
77
 For major neurocognitive disorder
 Probable alzheimer’s disease is diagnosed if either of the
following is present; otherwise, possible Alzheimer’s
disease should be diagnosed.
1. Evidence of a causative Alzheimer’s disease genetic
mutation from family history or genetic testing.
2. All 3 of the following are present:
A. Clear evidence of decline in memory and learning and
at least one other cognitive domain.
B. Steadily progressive, gradual decline in cognition,
without extended plateaus.
C. No evidence of mixed etiology
78
 For mild neurocognitive disorder
 Probable alzheimer’s disease is diagnosed if Evidence of a
causative Alzheimer’s disease genetic mutation from family
history or genetic testing.
 Possible alzheimer’s disease is diagnosed if there is no
Evidence of a causative Alzheimer’s disease genetic
mutation from family history or genetic testing.
DIAGNOSIS
(ALZHEIMERS ASSOCIATION 2011)
 3 stages of AD
 Preclinical AD requires measureable changes in
biomarkers and/or poor performance on challenging
cognitive tests.
 MCI - mild changes in memory and other cognitive
abilities; these changes can be detected through careful
evaluation, but do not interfere with day-to-day activities.
 Dementia - changes in two or more aspects of cognition
and behaviour that interfere with function in everyday life.
Alzheimer’s & Dementia 7 (2011) 257–262
79
DIFFERENTIAL DIAGNOSIS
 Dementias of other types
 Delirium
 Depression
 Schizophrenia
 Normal ageing
 Mental retardation
80
S.N Pseudodementia Dementia
1 Informant aware of memory disturbance
and can date the onset accurately
Onset is insidious and informant usually can
not date onset.
2 Patient complains enthusiastically about
the memory loss
Unlikely
3 Questions about cognitive functions lead
to DON’T KNOW RESPONSE
accompanied by irritation
Try their best but are incorrect
4 History is usually short and often there is
a previous history of depressive episode
History is long and depressive episode may
or may not be present
5 Depressed patients perform better on
memory tests.
Don’t perform well.
6 Memory complains are accompanied by
insomnia, diurnal variation etc.
May or may not be present
81
Feature Dementia Delirium
Onset Insidious Sudden
Duration Months to years Hours to week
Attention Preserved Fluctuates
Memory Impaired Impaired recent and
immediate
Speech Word finding difficulty Incoherent
Sleep & wake cycle Fragmented sleep Disrupted sleep, day night
reversal
Thoughts Impoverished Disorganized
Awareness Unchanged Reduced
Alertness Usually normal Hypervigilant or reduced
vigilance
82
83
Characteristics Alzheimer’s Disease Vascular Dementia
Sex Women Men
Age Generally over age 75 years Generally over age 60 years
Onset & progression Gradually progressive Episodic with stepwise
deterioration
History of hypertension Less common Common
History of stroke(s),transient
ischemic attack(s),or other
focal neurological symptoms
Less common Common
Hypertension Less common Common
Focal neurological signs Uncommon Common
Emotional lability Less common More common
Cognitive deficits Uniform patchy
Features Pick’s disease AD
Personality change Early Late
Amnesia Late Early
Language disturbances Early Late
Stereotypes Early Mid or late
Apraxia, agnosia, alexia Late Variable
Kluver-Bucy syndrome Early Late
Visuospatial disorientation Rare Common
Age of risk Mean 50, up to 80yrs Risk increases with age
CT Scan Fronto-Temporal atrophy Widespread atrophy
Gross Pathology Anterior hemi. Atrophy, Posterior hemispheric
atrophy,
Histopathology pick’s body Neurofibrillary tangle
84
MANAGEMENT
85
MANAGMENT
 Treatment of AD
 Treatment of secondary symptoms
 Experimental therapy
 Preventive measures
86
Treatment of AD
 Cholineesterase inhibitors - mild-moderate AD
 Donepezil
 Rivastigmine
 Galantamine
 NMDA antagonists – severe AD
 Memantine
87
88
Characteristic DONEPAZIL RIVASTIGMINE GALANTAMINE MEMANTINE
Chemical class Piperidine Carbamate Phenanthrene
alkaloid
Similar to
amantadine
Primary
mechanism
AchE inh AchE inh AchE inh NMDA
antagonist
Other
mechanism
None BuchE IN Nicotine
modulator
HT3 receptor
antagonist
Half life 70 h 90 min 7 h 70 h
Metabolism Hepatic Renal Hepatic Hepatic
Current status of AChE Inhibitors
 Treatment over 6 month produce improvement in cognitive
function.
 Benefits were also noted on ADL and behaviour.
 Direct comparison – equivocal result.
 Delay institutionalization
 Decrease troublesome behaviours
 Combining memantine with AChE inhibitors - slowed
cognitive and functional decline.
89
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
90
TREATMENT OF SECONDARY SYMPTOMS
 Neuroleptic agents
 FDA in 2005 black box warning for atypical neuroleptics
 2008 - haloperidol, chlorpromazine and thioridazine
included
 Typical antipsychotics – cardiac arrythmia and EPS
 Atypical – thromboembolism and aspirational pnemonia.
 Cognitive decline with both
91
 Antidepressants
 Sertaline & fluvoxetine – no benefits (wintraub & petrecca
et al study)
 Mirtazipine has no benefial effect ( Banerjee et al)
 Recommendation – not effective – not recommended.
 Anticonvulsants
 Very limited evidence to support use
92
EXPERIMENTAL THERAPY
93
94
 To date there is no effective approach in terms of cure or
prevention of dementia.
 The available pharmacological therapy is largely
symptomatic, with temporary clinical benefits on
cognitive, functional and behavioural manifestations of
the disease.
 There is an urgent need to develop new drugs with
disease-modifying properties for AD.
95
 A disease-modifying drug is a agent intended to slow
the progression of the neurodegenerative process by
inhibiting critical events in the pathophysiology of the
disease.
 Patients treated with such agents would be expected to
have a more benign course of the disease when
compared to placebo-treated individuals
96
 Many drugs have been proposed and tested in
neurobiological models of AD.
 However, the promising effects of these compounds
in animal models failed to prove beneficial to
humans.
 In addition, other drugs that underwent clinical
experimentation delivered negative results, either
due to limited efficacy or toxicity.
97
98
Therapeutic targets for disease
modification in AD
99
 More than 200 pharmaceutical compounds are
currently undergoing phase 2 and 3 trials.
 Grossly divided into :
 Anti amyloid
 Drug that target other pathways
Anti-amyloid compound
100
1. Block/inhibit the overproduction or aggregation
 Gamma secretase inhibitors
 Beta secretase inhibitors
2. Favour its clearance from the brain
 Active immunisation
 Passive immunisation
101
102
ACTIVE IMMUNIZATION
103
 Induces an IgM response to generate antibodies against
pathogenic Aβ, which further mobilize microglia to clean
plaques through phagocytosis
 AN 1792 – PHASE 2
 The trial was interrupted due to the occurrence of
meningoencephalitis in 6% of subjects.
 CAD106 - PHASE 1
 Able to reduce Aβ accumulation in cortical and subcortical
brain regions
Bioorg Med Chem Lett 2011; 21 : 2655-8.
S, Jacobson LH, et al.. J Neurosci 2011; 31 : 9323-31.
PASSIVE IMMUNISATION
104
 Intravenous administration of full monoclonal
antibodies or antibody fragments which directly
target Aβ.
 BAPINEUZUMAB
 Undergoing phase 3 studies.
 Researchers reported that it failed to protect against
cognitive and functional decline of AD patients undergoing
a phase 3 trial.
Neurology 2009; 73 : 2061-70.
105
 SOLANEZUMAB
 Phase 3 trials failed to demonstrate clinical benefits.
 But In a study conducted in Japan with AD patients
associated with increased clearance of Aβ from the brain.
 PONEZUMAB
 Targets the amino-terminal portion of Aβ1-40
 Phase 2 studies did not confirm clinical efficacy.
The European Federation of Neurological Societies annual 23. meeting, in Stokholm, Sweden; 2012.
Clin Neuropharmacol 2013; 36 : 14-23.
Inhibitor of production and accumulation
of Aβ
106
 γ-secretase inhibitors
 Semagacestat –
 Phase III trials found no efficacy.
 Even it was associated with increasing cognitive
impairment and worsening daily living activities, as well
with increasing risk for skin cancer.
 Avagacestat –
 Inhibitor of Ab 40 and Ab 42 formation
 Phase 2 study
Tau-oriented strategies
107
 LITHIUM AND VALPROATE - Inhibit GSK – prevent Tau
phosphorylation in animal models
 Valproate was not associated with reduction of cognitive or
functional decline.
 Long-term lithium treatment was associated with
stabilization of cognitive and functional parameters, in
addition to a reduction in CSF concentrations of
phosphorylated Tau.
 Phase 2 study in patients with mild AD treated with lithium
for a shorter (10 wk) period, no significant differences were
observed in biological or clinical outcomes.
Neurology 2011; 77 : 1263-71.
J Clin Psychiatry 2009; 70 : 922-31
Br J Psychiatry 2011; 198 : 351-6.
108
Others
109
 Ginkgo biloba
 Previously - effective in mild to moderate Alzheimer’s
disease with an advantage over placebo.
 Recent cochrane review – no evidence of efficacy
 Several reports of bleeding.
Pharmacopsychiatry 2003; 36:297–303.
Cochrane Database Syst Rev 2009; 1:CD003120
Antibiotics
 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
110
 Standardized ADAS Cog significant @ 6 but not 12 months
 Standardized MMSE score 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
111
 vitamin E
 High dose Vit E (2000U/day) for 2 yr slowed progression of
AD ( large double blind placebo trial ,Sano et al 1997)
 Alzheimer Disease Cooperative Study ( 769 pts) showed no
benefit vs placebo (Peterson et al 2005)
 Cause cardiovascular side effects
 Not recommended currently
112
Cochrane Database Syst Rev 2008; 3:CD002854.
 Estrogen replacement therapy
 RCT with 351 pts for 2 weeks showed no beneficial effects
 Cholesterol lowering agents
 RCT, double blinded study with 748 pts for 6 months failed
to prove efficacy
113
McGuinness B et al. Statins for the treatment of dementia. Cochrane
Database Syst Rev 2010; 8:CD007514.
 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.
114
115
 Omega-3 supplementation
 174 patients in a placebo-controlled RCT
 No significant overall effects on neuropsychiatric
symptoms, on ADL or on caregiver’s burden
 Positive effects were seen on depressive symptoms
Freund-Levi Y et al. Int J Geriatr Psychiatry 2008; 23:161–169.
116
 Dimebon (latrepirdine)
 Non-selective antihistamine previously approved in Russia
 Weak inhibitor of BuchE and AchE , weakly blocks the
NMDA receptor signalling pathway.
 A company sponsored study completed in Russia included
183 patients - significant benefits compared with placebo.
 In the recent CONNECTION study, dimebon was not more
effective than placebo.
Doody RS et al. Lancet 2008; 372:207–215.
117
 Huperzine A
 Alkaloid isolated from the Chinese herb Huperzia serrata
 AChE inhibitor used since 1994 in China.
 A recent meta-analysis found that huperzine A 300–500 g
daily for 8–24 weeks in Alzheimer’s disease led to
significant improvements in MMSE and ADL.
Wang BS et al. J Neural Transm 2009; 116:457–465.
118
 Cerebrolysin
 Porcine brain-derived peptide
 Cerebrolysin was superior to placebo in improving
global outcome measures and cognitive ability in
several RCTs of up to 28 weeks.
 A large RCT comparing cerebrolysin, donepezil or
combination therapy showed beneficial effects on
global measures and cognition for all three treatment
groups compared with baseline.
Plosker GL et al. Spotlight on cerebrolysin in dementia. CNS Drugs
2010; 24:263–266.
STEM CELL THERAPY
 South Florida university
 Mouse model study in 2009
 Several infusions of stem cells from umblical cord
 Myeloid protein reduced by 62%
 Cerebral amyloid angiopathy reduced by 82%
 Hope to begin human trials.
119
Conclusions
120
 Most phase 3 trials with candidate drugs for AD in the
last decade failed to present unequivocal clinical
benefits, or were suspended due to severe adverse
events.
 To date, treatment of AD relies on the symptomatic
effects of cholinesterase inhibitors and NMDA-receptor
antagonists.
Preventive measures
121
 Exercise regularly
 Eat a healthy diet rich in fruits and vegetables
 Engage in social and intellectually stimulating
activities
 Control type 2 diabetes
 Lower high blood pressure levels
122
 Lower high blood cholesterol levels
 Maintain a healthy weight
 Stop smoking
 Get treatment for depression
THANK YOU
123

Más contenido relacionado

La actualidad más candente

NEURODEGENERATIVE DISORDERS
NEURODEGENERATIVE DISORDERSNEURODEGENERATIVE DISORDERS
NEURODEGENERATIVE DISORDERSMariya Raju
 
ALZHEIMER DISEASE.pdf
ALZHEIMER DISEASE.pdfALZHEIMER DISEASE.pdf
ALZHEIMER DISEASE.pdfAmeena Kadar
 
Alzheimer's disease : Overview, Symptoms, Risk Factor, Causes, Treatment and ...
Alzheimer's disease : Overview, Symptoms, Risk Factor, Causes, Treatment and ...Alzheimer's disease : Overview, Symptoms, Risk Factor, Causes, Treatment and ...
Alzheimer's disease : Overview, Symptoms, Risk Factor, Causes, Treatment and ...Lazoi Lifecare Private Limited
 
Alzheimer’s disease ppt
Alzheimer’s disease pptAlzheimer’s disease ppt
Alzheimer’s disease pptFariha Shikoh
 
Alzheimer’s Disease
Alzheimer’s DiseaseAlzheimer’s Disease
Alzheimer’s Diseasehulyadiels
 
Alzheimer disease
Alzheimer disease Alzheimer disease
Alzheimer disease Tarek Gouda
 
Alzheimer’s disease ppt
Alzheimer’s disease pptAlzheimer’s disease ppt
Alzheimer’s disease pptfariha fatima
 
Alzheimer's disease
Alzheimer's diseaseAlzheimer's disease
Alzheimer's diseasecalvsh
 
Alzheimer powerpoint
Alzheimer powerpointAlzheimer powerpoint
Alzheimer powerpointJohnSmith2B1G
 
Pathophysiology and management of alzheimer's disease
Pathophysiology and management of alzheimer's diseasePathophysiology and management of alzheimer's disease
Pathophysiology and management of alzheimer's diseaseSoujanya Pharm.D
 
Alzheimer's Disease and its pathophysiology
Alzheimer's Disease and its pathophysiologyAlzheimer's Disease and its pathophysiology
Alzheimer's Disease and its pathophysiologyAchyut Adhikari
 
Dementia ppt. DR HUDA BUKHARI
Dementia ppt. DR HUDA BUKHARIDementia ppt. DR HUDA BUKHARI
Dementia ppt. DR HUDA BUKHARInajamsaqib41
 
Alzheimer's disease
Alzheimer's disease Alzheimer's disease
Alzheimer's disease SwalihaK
 
Alzheimer’s Disease - Causes, Symptoms & Treatment
Alzheimer’s Disease - Causes, Symptoms & TreatmentAlzheimer’s Disease - Causes, Symptoms & Treatment
Alzheimer’s Disease - Causes, Symptoms & Treatmentakajay201988
 

La actualidad más candente (20)

Alzheimers
AlzheimersAlzheimers
Alzheimers
 
NEURODEGENERATIVE DISORDERS
NEURODEGENERATIVE DISORDERSNEURODEGENERATIVE DISORDERS
NEURODEGENERATIVE DISORDERS
 
Alzheimer's disease
Alzheimer's diseaseAlzheimer's disease
Alzheimer's disease
 
ALZHEIMER DISEASE.pdf
ALZHEIMER DISEASE.pdfALZHEIMER DISEASE.pdf
ALZHEIMER DISEASE.pdf
 
Alzheimer's disease : Overview, Symptoms, Risk Factor, Causes, Treatment and ...
Alzheimer's disease : Overview, Symptoms, Risk Factor, Causes, Treatment and ...Alzheimer's disease : Overview, Symptoms, Risk Factor, Causes, Treatment and ...
Alzheimer's disease : Overview, Symptoms, Risk Factor, Causes, Treatment and ...
 
Alzheimer’s disease ppt
Alzheimer’s disease pptAlzheimer’s disease ppt
Alzheimer’s disease ppt
 
Alzheimer’s Disease
Alzheimer’s DiseaseAlzheimer’s Disease
Alzheimer’s Disease
 
Alzheimer disease
Alzheimer disease Alzheimer disease
Alzheimer disease
 
Alzheimer’s disease ppt
Alzheimer’s disease pptAlzheimer’s disease ppt
Alzheimer’s disease ppt
 
Alzheimer's disease
Alzheimer's diseaseAlzheimer's disease
Alzheimer's disease
 
Alzheimer
AlzheimerAlzheimer
Alzheimer
 
Alzheimer powerpoint
Alzheimer powerpointAlzheimer powerpoint
Alzheimer powerpoint
 
Alzheimer disease
Alzheimer diseaseAlzheimer disease
Alzheimer disease
 
Pathophysiology and management of alzheimer's disease
Pathophysiology and management of alzheimer's diseasePathophysiology and management of alzheimer's disease
Pathophysiology and management of alzheimer's disease
 
Alzheimer's disease
Alzheimer's diseaseAlzheimer's disease
Alzheimer's disease
 
Alzheimer's Disease and its pathophysiology
Alzheimer's Disease and its pathophysiologyAlzheimer's Disease and its pathophysiology
Alzheimer's Disease and its pathophysiology
 
Dementia ppt. DR HUDA BUKHARI
Dementia ppt. DR HUDA BUKHARIDementia ppt. DR HUDA BUKHARI
Dementia ppt. DR HUDA BUKHARI
 
Alzheimer's disease
Alzheimer's disease Alzheimer's disease
Alzheimer's disease
 
Alzheimers disease
Alzheimers diseaseAlzheimers disease
Alzheimers disease
 
Alzheimer’s Disease - Causes, Symptoms & Treatment
Alzheimer’s Disease - Causes, Symptoms & TreatmentAlzheimer’s Disease - Causes, Symptoms & Treatment
Alzheimer’s Disease - Causes, Symptoms & Treatment
 

Destacado

Alzheimer's disease
Alzheimer's diseaseAlzheimer's disease
Alzheimer's diseasejusiin
 
UCSD Alzheimer's Disease Presentation
UCSD Alzheimer's Disease PresentationUCSD Alzheimer's Disease Presentation
UCSD Alzheimer's Disease PresentationGlennerCenters
 
Alzheimer's disease
Alzheimer's diseaseAlzheimer's disease
Alzheimer's diseaseMerin Babu
 
Alzheimer's disease
Alzheimer's diseaseAlzheimer's disease
Alzheimer's diseaseIqra Altaf
 
Alzheimer’s disease: Management
Alzheimer’s disease: ManagementAlzheimer’s disease: Management
Alzheimer’s disease: ManagementReynel Dan
 
Reisa Sperling Preclinical Criteria Alzforum
Reisa Sperling Preclinical Criteria AlzforumReisa Sperling Preclinical Criteria Alzforum
Reisa Sperling Preclinical Criteria AlzforumAlzforum
 
Targets for the treatment of Alzheimer's disease
Targets for the treatment of Alzheimer's diseaseTargets for the treatment of Alzheimer's disease
Targets for the treatment of Alzheimer's diseaseBSAppleby
 
Prevention of Patient Falls - A Case Study
Prevention of Patient Falls - A Case StudyPrevention of Patient Falls - A Case Study
Prevention of Patient Falls - A Case StudyApollo Hospitals
 
Brain exercise for Improving cognitive functions
Brain exercise for Improving cognitive functionsBrain exercise for Improving cognitive functions
Brain exercise for Improving cognitive functionsarunmarvel6
 
Psychometric assessment of older adults oct 21 to 26 2013 winter workshop
Psychometric assessment of older adults oct 21 to 26 2013 winter workshopPsychometric assessment of older adults oct 21 to 26 2013 winter workshop
Psychometric assessment of older adults oct 21 to 26 2013 winter workshopDr. Rakesh Tripathi
 
Growth of Nanomedicine Market in a new 2016 report
Growth of Nanomedicine Market in a new 2016 reportGrowth of Nanomedicine Market in a new 2016 report
Growth of Nanomedicine Market in a new 2016 reportPete Jones
 
Alzheimer's Disease Final Presentation
Alzheimer's Disease Final PresentationAlzheimer's Disease Final Presentation
Alzheimer's Disease Final PresentationMelissa McCoy, MS, MBA
 
Study of alzheimer's disease using knock in mouse model
Study of alzheimer's disease using knock in mouse modelStudy of alzheimer's disease using knock in mouse model
Study of alzheimer's disease using knock in mouse modelChristin Wong Ching Yee
 
Sedatives hypnotic
Sedatives hypnoticSedatives hypnotic
Sedatives hypnoticKef Barobi
 

Destacado (20)

Alzheimer's disease
Alzheimer's diseaseAlzheimer's disease
Alzheimer's disease
 
Alzheimer's disease
Alzheimer's diseaseAlzheimer's disease
Alzheimer's disease
 
UCSD Alzheimer's Disease Presentation
UCSD Alzheimer's Disease PresentationUCSD Alzheimer's Disease Presentation
UCSD Alzheimer's Disease Presentation
 
Alzheimer's disease
Alzheimer's diseaseAlzheimer's disease
Alzheimer's disease
 
Robbins Alzheimers Dementia Toma 2006
Robbins Alzheimers Dementia Toma 2006Robbins Alzheimers Dementia Toma 2006
Robbins Alzheimers Dementia Toma 2006
 
Alzheimer's disease
Alzheimer's diseaseAlzheimer's disease
Alzheimer's disease
 
Alzheimer’s disease: Management
Alzheimer’s disease: ManagementAlzheimer’s disease: Management
Alzheimer’s disease: Management
 
Reisa Sperling Preclinical Criteria Alzforum
Reisa Sperling Preclinical Criteria AlzforumReisa Sperling Preclinical Criteria Alzforum
Reisa Sperling Preclinical Criteria Alzforum
 
Current Issues in the Diagnosis and Treatment of Alzheimer's
Current Issues in the Diagnosis and Treatment of Alzheimer'sCurrent Issues in the Diagnosis and Treatment of Alzheimer's
Current Issues in the Diagnosis and Treatment of Alzheimer's
 
Targets for the treatment of Alzheimer's disease
Targets for the treatment of Alzheimer's diseaseTargets for the treatment of Alzheimer's disease
Targets for the treatment of Alzheimer's disease
 
nanomedicine
nanomedicinenanomedicine
nanomedicine
 
Prevention of Patient Falls - A Case Study
Prevention of Patient Falls - A Case StudyPrevention of Patient Falls - A Case Study
Prevention of Patient Falls - A Case Study
 
Brain exercise for Improving cognitive functions
Brain exercise for Improving cognitive functionsBrain exercise for Improving cognitive functions
Brain exercise for Improving cognitive functions
 
Psychometric assessment of older adults oct 21 to 26 2013 winter workshop
Psychometric assessment of older adults oct 21 to 26 2013 winter workshopPsychometric assessment of older adults oct 21 to 26 2013 winter workshop
Psychometric assessment of older adults oct 21 to 26 2013 winter workshop
 
6. age
6. age6. age
6. age
 
Growth of Nanomedicine Market in a new 2016 report
Growth of Nanomedicine Market in a new 2016 reportGrowth of Nanomedicine Market in a new 2016 report
Growth of Nanomedicine Market in a new 2016 report
 
Alzheimer's Disease Final Presentation
Alzheimer's Disease Final PresentationAlzheimer's Disease Final Presentation
Alzheimer's Disease Final Presentation
 
Study of alzheimer's disease using knock in mouse model
Study of alzheimer's disease using knock in mouse modelStudy of alzheimer's disease using knock in mouse model
Study of alzheimer's disease using knock in mouse model
 
Mine ap
Mine apMine ap
Mine ap
 
Sedatives hypnotic
Sedatives hypnoticSedatives hypnotic
Sedatives hypnotic
 

Similar a Alzheimers disease

Alzheimer's disease - A detailed case study
Alzheimer's disease - A detailed case study Alzheimer's disease - A detailed case study
Alzheimer's disease - A detailed case study Uzair Ahmed
 
2011018955 T.Mooko
2011018955 T.Mooko2011018955 T.Mooko
2011018955 T.MookoTeboho Mooko
 
Autism spectrum disorder
Autism spectrum disorderAutism spectrum disorder
Autism spectrum disorderEnoch R G
 
Mark Daly - Finding risk genes in psychiatric disorders
Mark Daly - Finding risk genes in psychiatric disordersMark Daly - Finding risk genes in psychiatric disorders
Mark Daly - Finding risk genes in psychiatric disorderswef
 
ALZHEIMERS DEMENTIA-PATHOLOGY AND PATHOPHYSIOLOGY.pptx
ALZHEIMERS DEMENTIA-PATHOLOGY AND PATHOPHYSIOLOGY.pptxALZHEIMERS DEMENTIA-PATHOLOGY AND PATHOPHYSIOLOGY.pptx
ALZHEIMERS DEMENTIA-PATHOLOGY AND PATHOPHYSIOLOGY.pptxsarathchandran951352
 
A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...
A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...
A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...Dr. Rafael Higashi
 
The neurobiology of everyday life final project
The neurobiology of everyday life  final projectThe neurobiology of everyday life  final project
The neurobiology of everyday life final projectAleksandra Włodarczyk
 
The comprehensive guide to autism
The comprehensive guide to autismThe comprehensive guide to autism
The comprehensive guide to autismSpringer
 
4-30-15_Luisanna_MQP_Final
4-30-15_Luisanna_MQP_Final4-30-15_Luisanna_MQP_Final
4-30-15_Luisanna_MQP_FinalLuisanna Paulino
 
ageing final.pptx
ageing final.pptxageing final.pptx
ageing final.pptxanintamelie
 
Genetics in dementia
Genetics in dementiaGenetics in dementia
Genetics in dementiaRavi Soni
 

Similar a Alzheimers disease (20)

Prader Willi Syndrome ppt1
Prader Willi Syndrome ppt1Prader Willi Syndrome ppt1
Prader Willi Syndrome ppt1
 
Alzheimer's disease - A detailed case study
Alzheimer's disease - A detailed case study Alzheimer's disease - A detailed case study
Alzheimer's disease - A detailed case study
 
Alzheimer disease (ad)
Alzheimer disease (ad)Alzheimer disease (ad)
Alzheimer disease (ad)
 
2011018955 T.Mooko
2011018955 T.Mooko2011018955 T.Mooko
2011018955 T.Mooko
 
Autism spectrum disorder
Autism spectrum disorderAutism spectrum disorder
Autism spectrum disorder
 
Alzheimers Diseases
Alzheimers DiseasesAlzheimers Diseases
Alzheimers Diseases
 
Schizophrenia
SchizophreniaSchizophrenia
Schizophrenia
 
Lit Review
Lit ReviewLit Review
Lit Review
 
Epidemic Influences
Epidemic InfluencesEpidemic Influences
Epidemic Influences
 
Mark Daly - Finding risk genes in psychiatric disorders
Mark Daly - Finding risk genes in psychiatric disordersMark Daly - Finding risk genes in psychiatric disorders
Mark Daly - Finding risk genes in psychiatric disorders
 
ALZHEIMERS DEMENTIA-PATHOLOGY AND PATHOPHYSIOLOGY.pptx
ALZHEIMERS DEMENTIA-PATHOLOGY AND PATHOPHYSIOLOGY.pptxALZHEIMERS DEMENTIA-PATHOLOGY AND PATHOPHYSIOLOGY.pptx
ALZHEIMERS DEMENTIA-PATHOLOGY AND PATHOPHYSIOLOGY.pptx
 
A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...
A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...
A guideline for discontinuing antiepileptic drugs in seizure-free patients – ...
 
An Interlude: Hypertension – Alzheimer’s
An Interlude: Hypertension – Alzheimer’sAn Interlude: Hypertension – Alzheimer’s
An Interlude: Hypertension – Alzheimer’s
 
psychosis 8.ppt
psychosis   8.pptpsychosis   8.ppt
psychosis 8.ppt
 
Schizophrenia
SchizophreniaSchizophrenia
Schizophrenia
 
The neurobiology of everyday life final project
The neurobiology of everyday life  final projectThe neurobiology of everyday life  final project
The neurobiology of everyday life final project
 
The comprehensive guide to autism
The comprehensive guide to autismThe comprehensive guide to autism
The comprehensive guide to autism
 
4-30-15_Luisanna_MQP_Final
4-30-15_Luisanna_MQP_Final4-30-15_Luisanna_MQP_Final
4-30-15_Luisanna_MQP_Final
 
ageing final.pptx
ageing final.pptxageing final.pptx
ageing final.pptx
 
Genetics in dementia
Genetics in dementiaGenetics in dementia
Genetics in dementia
 

Más de Karrar Husain

Prognosis of schizophrenia
Prognosis of schizophreniaPrognosis of schizophrenia
Prognosis of schizophreniaKarrar Husain
 
Atypical antipsychotics
Atypical antipsychoticsAtypical antipsychotics
Atypical antipsychoticsKarrar Husain
 
Sleep disorders and psychiatry
Sleep disorders and psychiatrySleep disorders and psychiatry
Sleep disorders and psychiatryKarrar Husain
 
Limbic system and psychiatric disorders
Limbic system and psychiatric disordersLimbic system and psychiatric disorders
Limbic system and psychiatric disordersKarrar Husain
 
Etiology of substance use
Etiology of substance useEtiology of substance use
Etiology of substance useKarrar Husain
 
Biological basis of memory
Biological basis of memoryBiological basis of memory
Biological basis of memoryKarrar Husain
 
Acute and transient psychotic disorders
Acute and transient psychotic disordersAcute and transient psychotic disorders
Acute and transient psychotic disordersKarrar Husain
 
Neurobiology of stress
Neurobiology of stressNeurobiology of stress
Neurobiology of stressKarrar Husain
 
Functional neuroanatomy of brain
Functional neuroanatomy    of brainFunctional neuroanatomy    of brain
Functional neuroanatomy of brainKarrar Husain
 

Más de Karrar Husain (10)

Prognosis of schizophrenia
Prognosis of schizophreniaPrognosis of schizophrenia
Prognosis of schizophrenia
 
Atypical antipsychotics
Atypical antipsychoticsAtypical antipsychotics
Atypical antipsychotics
 
Sleep disorders and psychiatry
Sleep disorders and psychiatrySleep disorders and psychiatry
Sleep disorders and psychiatry
 
Limbic system and psychiatric disorders
Limbic system and psychiatric disordersLimbic system and psychiatric disorders
Limbic system and psychiatric disorders
 
Etiology of substance use
Etiology of substance useEtiology of substance use
Etiology of substance use
 
Delirium
DeliriumDelirium
Delirium
 
Biological basis of memory
Biological basis of memoryBiological basis of memory
Biological basis of memory
 
Acute and transient psychotic disorders
Acute and transient psychotic disordersAcute and transient psychotic disorders
Acute and transient psychotic disorders
 
Neurobiology of stress
Neurobiology of stressNeurobiology of stress
Neurobiology of stress
 
Functional neuroanatomy of brain
Functional neuroanatomy    of brainFunctional neuroanatomy    of brain
Functional neuroanatomy of brain
 

Último

blood bank management system project report
blood bank management system project reportblood bank management system project report
blood bank management system project reportNARMADAPETROLEUMGAS
 
Male Infertility Panel Discussion by Dr Sujoy Dasgupta
Male Infertility Panel Discussion by Dr Sujoy DasguptaMale Infertility Panel Discussion by Dr Sujoy Dasgupta
Male Infertility Panel Discussion by Dr Sujoy DasguptaSujoy Dasgupta
 
Pharmacokinetic Models by Dr. Ram D. Bawankar.ppt
Pharmacokinetic Models by Dr. Ram D.  Bawankar.pptPharmacokinetic Models by Dr. Ram D.  Bawankar.ppt
Pharmacokinetic Models by Dr. Ram D. Bawankar.pptRamDBawankar1
 
power point presentation of Clinical evaluation of strabismus
power point presentation of Clinical evaluation  of strabismuspower point presentation of Clinical evaluation  of strabismus
power point presentation of Clinical evaluation of strabismusChandrasekar Reddy
 
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdfSGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdfHongBiThi1
 
Adenomyosis or Fibroid- making right diagnosis
Adenomyosis or Fibroid- making right diagnosisAdenomyosis or Fibroid- making right diagnosis
Adenomyosis or Fibroid- making right diagnosisSujoy Dasgupta
 
Unit I herbs as raw materials, biodynamic agriculture.ppt
Unit I herbs as raw materials, biodynamic agriculture.pptUnit I herbs as raw materials, biodynamic agriculture.ppt
Unit I herbs as raw materials, biodynamic agriculture.pptPradnya Wadekar
 
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptxANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptxWINCY THIRUMURUGAN
 
Clinical Research Informatics Year-in-Review 2024
Clinical Research Informatics Year-in-Review 2024Clinical Research Informatics Year-in-Review 2024
Clinical Research Informatics Year-in-Review 2024Peter Embi
 
Basic structure of hair and hair growth cycle.pptx
Basic structure of hair and hair growth cycle.pptxBasic structure of hair and hair growth cycle.pptx
Basic structure of hair and hair growth cycle.pptxkomalt2001
 
historyofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusanguhistoryofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusangu Medical University
 
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...Shubhanshu Gaurav
 
Role of Soap based and synthetic or syndets bar
Role of  Soap based and synthetic or syndets barRole of  Soap based and synthetic or syndets bar
Role of Soap based and synthetic or syndets barmohitRahangdale
 
AORTIC DISSECTION and management of aortic dissection
AORTIC DISSECTION and management of aortic dissectionAORTIC DISSECTION and management of aortic dissection
AORTIC DISSECTION and management of aortic dissectiondrhanifmohdali
 
Mental health Team. Dr Senthil Thirusangu
Mental health Team. Dr Senthil ThirusanguMental health Team. Dr Senthil Thirusangu
Mental health Team. Dr Senthil Thirusangu Medical University
 
CPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing studentCPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing studentsaileshpanda05
 
AUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functionsAUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functionsMedicoseAcademics
 

Último (20)

blood bank management system project report
blood bank management system project reportblood bank management system project report
blood bank management system project report
 
Male Infertility Panel Discussion by Dr Sujoy Dasgupta
Male Infertility Panel Discussion by Dr Sujoy DasguptaMale Infertility Panel Discussion by Dr Sujoy Dasgupta
Male Infertility Panel Discussion by Dr Sujoy Dasgupta
 
How to master Steroid (glucocorticoids) prescription, different scenarios, ca...
How to master Steroid (glucocorticoids) prescription, different scenarios, ca...How to master Steroid (glucocorticoids) prescription, different scenarios, ca...
How to master Steroid (glucocorticoids) prescription, different scenarios, ca...
 
Pharmacokinetic Models by Dr. Ram D. Bawankar.ppt
Pharmacokinetic Models by Dr. Ram D.  Bawankar.pptPharmacokinetic Models by Dr. Ram D.  Bawankar.ppt
Pharmacokinetic Models by Dr. Ram D. Bawankar.ppt
 
power point presentation of Clinical evaluation of strabismus
power point presentation of Clinical evaluation  of strabismuspower point presentation of Clinical evaluation  of strabismus
power point presentation of Clinical evaluation of strabismus
 
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdfSGK ĐIỆN GIẬT ĐHYHN        RẤT LÀ HAY TUYỆT VỜI.pdf
SGK ĐIỆN GIẬT ĐHYHN RẤT LÀ HAY TUYỆT VỜI.pdf
 
Adenomyosis or Fibroid- making right diagnosis
Adenomyosis or Fibroid- making right diagnosisAdenomyosis or Fibroid- making right diagnosis
Adenomyosis or Fibroid- making right diagnosis
 
American College of physicians ACP high value care recommendations in rheumat...
American College of physicians ACP high value care recommendations in rheumat...American College of physicians ACP high value care recommendations in rheumat...
American College of physicians ACP high value care recommendations in rheumat...
 
Unit I herbs as raw materials, biodynamic agriculture.ppt
Unit I herbs as raw materials, biodynamic agriculture.pptUnit I herbs as raw materials, biodynamic agriculture.ppt
Unit I herbs as raw materials, biodynamic agriculture.ppt
 
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptxANATOMICAL FAETURES OF BONES  FOR NURSING STUDENTS .pptx
ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
 
Clinical Research Informatics Year-in-Review 2024
Clinical Research Informatics Year-in-Review 2024Clinical Research Informatics Year-in-Review 2024
Clinical Research Informatics Year-in-Review 2024
 
Basic structure of hair and hair growth cycle.pptx
Basic structure of hair and hair growth cycle.pptxBasic structure of hair and hair growth cycle.pptx
Basic structure of hair and hair growth cycle.pptx
 
historyofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusanguhistoryofpsychiatryinindia. Senthil Thirusangu
historyofpsychiatryinindia. Senthil Thirusangu
 
GOUT UPDATE AHMED YEHIA 2024, case based approach with application of the lat...
GOUT UPDATE AHMED YEHIA 2024, case based approach with application of the lat...GOUT UPDATE AHMED YEHIA 2024, case based approach with application of the lat...
GOUT UPDATE AHMED YEHIA 2024, case based approach with application of the lat...
 
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
FDMA FLAP - The first dorsal metacarpal artery (FDMA) flap is used mainly for...
 
Role of Soap based and synthetic or syndets bar
Role of  Soap based and synthetic or syndets barRole of  Soap based and synthetic or syndets bar
Role of Soap based and synthetic or syndets bar
 
AORTIC DISSECTION and management of aortic dissection
AORTIC DISSECTION and management of aortic dissectionAORTIC DISSECTION and management of aortic dissection
AORTIC DISSECTION and management of aortic dissection
 
Mental health Team. Dr Senthil Thirusangu
Mental health Team. Dr Senthil ThirusanguMental health Team. Dr Senthil Thirusangu
Mental health Team. Dr Senthil Thirusangu
 
CPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing studentCPR.nursingoutlook.pdf , Bsc nursing student
CPR.nursingoutlook.pdf , Bsc nursing student
 
AUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functionsAUTONOMIC NERVOUS SYSTEM organization and functions
AUTONOMIC NERVOUS SYSTEM organization and functions
 

Alzheimers disease

  • 1. ETIOPATHOGENESIS MANAGEMENT AND RECENT ADVANCES IN ALZHEIMERS DISEASE Presented by Dr. Karrar Husain Moderator – Dr. M. Amir Usmani 1
  • 2. 2  INTRODUCTION AND HISTORY  EPIDEMIOLOGY  ETIOPATHOGENESIS  ASSESMENT  DIAGNOSIS AND D/D  MANAGEMENT  PREVENTION
  • 4. INTRODUCTION  Alzheimer’s disease (AD) is the commonest progressive, dementing neurodegenerative disease in elderly, which affects innumerable people each year, and these numbers are likely to further increase as the population ages.  In addition to the financial burden of AD on health care system, the disease has powerful emotional impact on caregivers and families of those afflicted. 4
  • 5. BRIEF HISTORY  Alois Alzheimer, a German physician, is credited with being the first to describe AD.  In 1906, Dr. Alzheimer observed a patient, Auguste Deter, in a local asylum who exhibited strange behaviors. He followed her care and noted her memory loss, language difficulty and confusion. Alois Alzheimer 5
  • 6.  After her death at the age of 51, he examined her brain tissue. The slides showed what are now known as plaques and tangles.  In 1911, Doctors were using Dr. Alzheimer’s research to base diagnosis.  In the 1960’s British pathologists determined that AD was not a rare disease of the young but rather what had been termed “senility.”  In the 1990’s researchers identified that the beta amyloid protein was a factor in AD. 6
  • 7. 7
  • 9.  MC cause of dementia, > 65yr.  Starting with 0.5% prevalence at 55 yrs., it goes on doubling every five years (60yrs-1%; 65yrs. – 2%; 70 yrs. -4%; 75yrs.-8% and so on)  Risk at the age of 80 years is around 15 to 20%  About 7.7 million new cases of dementia each year. A new case detected in every 4 seconds somewhere in world. EPIDEMIOLOGY WHO 9
  • 10.  The incidence rates per 1000 person-years for AD was  11.67 for ≥55 years  15.54 for aged ≥65 years. Neurol India. 2012 Nov-Dec;60(6):625-30. doi: 10.4103/0028-3886.105198. 10
  • 11. COMMON TYPES OF DEMENTIAS Type of Dementia % in total Cases Alzheimer’s Dementia 50-55 Vascular Dementia 30-35 Lewy body Dementia 5-7 Pick’s Dementia 3-5 Other Dementias 10-15 11
  • 12. Ziegler-Graham K et al. Alzheimer’s & Dememtia 2007;3(Suppl):S168–9 New Estimate of Dementia Worldwide 12
  • 13. ALZHEIMER’S PREVALENCE Qui et al. (2009). Dialogues in Clinical Neuroscience, 11(2), 111-128. 13
  • 14. 14
  • 15. RISK FACTORS  Age : every 5 yr beyond 65, the % of people with AD doubles  Family history : strong genetic component 1. Early onset – fully penetrant 2. Late onset – reduced penetrant  Gender – women, ? Estrogen  Tobacco  Head injury 15
  • 16.  Obesity  Hypertension , diabetes  Elevated serum cholesterol  Elevated serum homocysteine  Depression  Lack of intellectual stimulation/education 16
  • 17. PROTECTIVE FACTORS  Physical activity  Caffeine consumption  Antioxidants – VITAMIN C, E, B6 and B12  Folate  N -3 fatty acid intake  Speaking > 2 language 17
  • 19.  AD is characterized by generalized cerebral cortical atrophy, neuronal loss, widespread cortical neuritic plaques and neurofibrillary tangles.  Following mechanisms have been attributed for the development of Alzheimer’s dementia  Amyloid cascade theory  Neuronal loss  Cholinergic hypothesis  Excitotoxicity  Genetic factors PATHOGENESIS AND PATHOPHYSIOLOGY 19
  • 20.  Alzheimer’s disease begins with the abnormal build-up of an amyloid protein in the brain from APP(amyloid precursor protein).  APP normally found in the cell membranes of neurons and normally metabolised by a protease enzyme α–secretase.  In AD, the metabolism of APP is altered by two other enzymes β and γ secretase and is called β amyloid (Aβ). AMYLOID CASCADE THEORY 20
  • 21.  Amyloid-β is originated by the alternative cleavage of the amyloid precursor protein (APP) into smaller peptides (Aβ1- 40 and Aβ1-42) by two other enzymes β and γ secretase  Aβ1-42 is more prone to form insoluble aggregates (and therefore more toxic) than Aβ1-40.  Once Aβ is formed, it accumulates into insoluble sheets (called β-pleated sheets). 21
  • 22.  The interaction between genetic and environmental factors, along with the homeostatic changes that pertain to the ageing, seems to affect the balance between production and clearance of toxic Aβ peptides.  These deposits are neurotoxic and activate inflammatory reaction resulting in the formation of senile or neuritic plaque.  This is accompanied by hyperphosphorylation of tau protein, supporting the microtubules. 22
  • 23.  Hyperphosphorylated Tau aggregates into oligomers to form NFTs.  Several protein kinases are involved in this process, namely glycogen synthase kinase-3 beta (GSK3β), cyclin-dependent kinase-5 (CDK5), and extracellular signal-related kinase-2 (ERK2).  GSK-3β, the most important Tau kinase in neurons, is overactive in AD 23 Journal of Alzheimer’s Disease 33 (2013) S185 -S194 DOI 10.3233/JAD-2012-129028
  • 24. 24
  • 25. 25
  • 26.  The classic gross neuro- anatomical observation is  Diffuse atrophy with widening cortical sulci  Enlarged cerebral ventricles.  There is a progressive loss of neurons and their supportive glial cells.  The loss is more marked in the entorhinal cortex, hippocampus and basal forebrain. NEURONAL LOSS 26
  • 27. Source: Image from the Alzheimer’s Society of Saskatchewan with permission from Alzheimer’s Broken Brain. Alzheimer’s Brain Normal Brain 27
  • 28. 28
  • 29.  Levels of acetylcholine, noradrenaline, serotonin, γ- aminobutyric acid (GABA), glutamate, somatostatin, neuropeptide Y, and substance P have all been documented to be reduced in the brains of AD patients.  Reductions in acetylcholine and choline acetyltransferase are the most profound.  Neuronal loss in the basal forebrain, which is the major region from which cholinergic projections originate. CHOLINERGIC HYPOTHESIS 29
  • 30.  Excessive release of glutamate into the synapses.  Excessive influx of calcium into the cells leading to cell death called excitotoxicity.  Also lead to excessive production of Aβ and tau phosphorylation. EXCITOTOXICITY 30
  • 31.  Growing evidence for the role of additional factors such as oxidative stress, neuroinflammation, and mitochondrial dysfunction in the pathogenesis of AD. 31
  • 32. GENETICS  Four genes 1. Presenelin 1- chr 14 2. Presenelin 2- chr 1 3. Amyloid beta protein precursor- chr 21 4. Apolipoprotien E gene – chr 19  Typically divided into – early onset and late onset Arch. Neurol. 1998;55:294-296 32
  • 33. GENETICS OF EARLY ONSET  APP gene  Increase the production of amyloid.  Age of onset range from – 39 to 68 yrs  6 different mutation – all are fully penetrant.  APOE-4 mutation further decrease the age of onset. Arch. Neurol. 1998;55:294-296 33
  • 34.  THE PRESENELIN GENES  Half of the early onset AD patient  Increase the production of amyloid and promote apoptosis.  It increase the production of Aß 1 -42,which is more hydrophobic more prone to agreggation, hence more toxic  All PS1 mutation are fully penetrant and autosomal dominant  Age of onset in PS1 mutation range from 32 to 56 yrs  Age of onset in PS2 mutation range from 40 – 85 yrs Arch. Neurol. 1998;55:294-296 34
  • 35. GENETICS OF LATE ONSET AD  APOE GENE  Has 3 alleles – 2,3 and 4…. 4 is associated with pathology  Normal gene promote proteolysis and clearence of amyloid, and mutant gene promote aggregation and deposition of amyloid.  Increase the risk of disease.  Age of onset 60s  It decrease the age of onset with APP mutation. Arch. Neurol. 1998;55:294-296 35
  • 36. 36
  • 38. SIGN AND SYMPTOMS OF AD 38
  • 39. Who should be evaluated for AD  Age more than 60yr  People with risk factors – head injury, CV risks  People with memory or cognitive complaints, with or without change in functioning.  Memory difficulty noted by friends, relatives or spouse.  Patient with depression or anxiety without memory complaints 39
  • 40. ASSESMENT  History 1. Patient 2. Relatives  Comprehensive physical and neurological examination  Cognitive evaluation  Functioning status  Lab work  Imaging 40
  • 41. HISTORY  Memory impairment – trouble remembering recent conversation, events, appointments, frequently misplaces objects.  Executive impairment – deterioration of complex task performance, decreased ability to solve problems, impaired driving.  DRUGS  Focal motor or sensory symptoms  Behavior personality and mood changes 41
  • 42. TOOLS Screening  Mini Mental State Examination (MMSE) (Folstein et al. 1975)  Hindi Mental State Examination (HMSE) (Ganguli et al. 1995)  Hindi Cognitive Screening Test (Tiwari and Tripathi, 2011)  St. Louis University Mental State (SLUMS) Exm. (JE Morley, 2000)  Clock Drawing Test (CDT) (Shulman et al. 1993)  Bender Gestalt Test (BGT) (Lauretta Bender, 1938)  Hachinski Ischemic Scale (1975) 42
  • 43. Detailed Assessment  Survey Psychiatric Assessment Schedule (Bond et al. 1980)  CAMDEX-R (Roth et al. 1986, 1998-R)  Alzheimer's Disease Assessment Scale (Rosen et al. 1984)  Schedule for Clinical Assessment in Neuropsychiatry (SCAN) (WHO, 1996)  Clinical Dementia Rating (Morris, 1993)  Blessed Dementia Scale (Blessed, 1968) 43
  • 44. Scoring: 0- 4: Severe, 5-14: Mod. 15-19: Mild Dementia; 20-24: MCI, 25-28 :Age related Cog Impairment, 29-30:Normal 44
  • 45. 45
  • 46. 46
  • 47. Features Score 1. Abrupt 2 2. Stepwise deterioration 1 3. Fluctuating course 2 4. Nocturnal confusion 1 5. Relative preservation of personality 1 6. Depression 1 7. Somatic Complaints 1 8. Emotional incontinence 1 Features Score 9. History or presence of hypertension 1 10. History of strokes 2 11. Evidence of associated atherosclerosis 1 12. Focal neurologic symptoms 2 13. Focal neurologic sign 2 Total Score 18 Hachinski Ischemic Scale (1975) Scoring 0-4: Alzheimer's Dementia; 5-6: diagnosis unclear; 7 or more : Vascular Dementia 47
  • 48. 48 Score Error(s) 1 No error 2 Minor visuospatial error 3 Inaccurate representation of “10 past 11” 4 Moderate visuospatial disorganization of times 5 Several disorganization 6 No reasonable representation of a clockScore≥ 3: Cognitive deficit CLOCK DRAWING TEST
  • 50. 50
  • 51. LABORATORY EAVALUATION  CBC, full chemistry, TSH.  Serum B12 and folic acid  No value of genetic testing at present  CSF markers – used only for research purpose not recommended for clinical diagnosis • Amyloid beta 42 - low • Total tau - elevated • Phosphorylated tau - elevated 51
  • 52.  CSF marker may assist in differentiating from other dementia.  A study in 2014 recommended the ratio of tau to A beta 42 with a cut of point of > 0.52 for differentiating AD from other dementia…its more sensitive than individual marker.  Its also important in predicting progression of MCI and dementia. F.H. Duits et al. / Alzheimer’s & Dementia -(2014) 1–11 52
  • 53. F.H. Duits et al. / Alzheimer’s & Dementia -(2014) 1–11 53
  • 54. IMAGING  STRUCTURAL IMAGING – CT, MRI  May reveal atrophy, white matter changes  Not sensitive/specific to AD.  In AD – diffuse cerebral atrophy, enlarged sulci, increased size of ventricles, loss of hippocampal volume. 54
  • 56.  FDG - PET  Functional imaging of brain metabolism.  It measures synaptic activity in different part of brain  In AD – temporal and parietal glucose hypometabolism.  Can differentiate AD from FTD.  IOFLUPANE  SPECT for evaluation of presynaptic dopamine transporters, useful in differentiating AD from lewy body dementia 56
  • 57. 57
  • 58. AMYLOID IMAGING  11C – labelled pittsburgh compound B  First PET ligand to visualise beta amyloid in living patient  It have short half life.  Flourine 18 agents have longer half life and FDA approved.  Sensitivity – 80 to 93%  Specificity – 91 to 96% 58
  • 59. 59
  • 60. PET TAU IMAGING  In vivo marker of abnormally phosphorylated TAU protein.  Tangles correlate best with cognitive impairment  Amyloid may be present for years in the absence of impairment  Combined amyloid and TAU imaging my help in early diagnosis and intervention. 60
  • 61. Alzheimer’s & Dementia 7 (2011) 257–262 61
  • 62. Alzheimer’s & Dementia 7 (2011) 257–262 62
  • 64. 64
  • 65. ETIOPATHOGENESIS MANAGEMENT AND RECENT ADVANCES IN ALZHEIMERS DISEASE Presented by Dr. Karrar Husain Moderator – Dr. M. Amir Usmani 65
  • 66. 66  INTRODUCTION AND HISTORY  EPIDEMIOLOGY  ETIOPATHOGENESIS  ASSESMENT  DIAGNOSIS AND D/D  MANAGEMENT  PREVENTION
  • 68. DSM 5 68  NEUROCOGNITIVE DIORDERS  DELIRIUM  MAJOR NEUROCOGNITIVE DISORDERS  MILD NEUROCOGNITIVE DISORDERS
  • 69. Mild NCD 69 A. Evidence of modest cognitive decline from a previous level of performance in one or more cognitive domains based on: 1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a mild decline in cognitive function; and 2. A modest impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment. B. The cognitive deficits do not interfere with capacity for independence in everyday activities
  • 70. 70 C. The cognitive deficits do not occur exclusively in the context of delirium. D. The cognitive deficits are not better explained by another mental disorder.  Specify:  Without behavioral disturbance  With behavioral disturbance
  • 71. 71  Specify whether due to  Alzheimer’s disease  FTD  LBD  Vascular  TBI  Substance/medication use  ………  Unspecified
  • 72. Major NCD 72 A. Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains based on: 1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a significant decline in cognitive function; and 2. A substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment. B. The cognitive deficits interfere with independence in everyday activities.
  • 73. 73 C. The cognitive deficits do not occur exclusively in the context of delirium. D. The cognitive deficits are not better explained by another mental disorder.  Specify:  Without behavioral disturbance  With behavioral disturbance
  • 74. 74  Specify whether due to  Alzheimer’s disease  FTD  LBD  Vascular  TBI  Substance/medication use  ………  Unspecified
  • 75. 75  Specify current severity  Mild  Moderate  Severe
  • 76. Major or Mild NCD Due to Alzheimer’s 76 A. The criteria are met for major or mild neurocognitive disorder. B. There is insidious onset and gradual progression of impairment in one or more cognitive domains. C. Criteria are met for either probable or possible Alzheimer’s disease as follows:  For major neurocognitive disorder  For mild neurocognitive disorder
  • 77. 77  For major neurocognitive disorder  Probable alzheimer’s disease is diagnosed if either of the following is present; otherwise, possible Alzheimer’s disease should be diagnosed. 1. Evidence of a causative Alzheimer’s disease genetic mutation from family history or genetic testing. 2. All 3 of the following are present: A. Clear evidence of decline in memory and learning and at least one other cognitive domain. B. Steadily progressive, gradual decline in cognition, without extended plateaus. C. No evidence of mixed etiology
  • 78. 78  For mild neurocognitive disorder  Probable alzheimer’s disease is diagnosed if Evidence of a causative Alzheimer’s disease genetic mutation from family history or genetic testing.  Possible alzheimer’s disease is diagnosed if there is no Evidence of a causative Alzheimer’s disease genetic mutation from family history or genetic testing.
  • 79. DIAGNOSIS (ALZHEIMERS ASSOCIATION 2011)  3 stages of AD  Preclinical AD requires measureable changes in biomarkers and/or poor performance on challenging cognitive tests.  MCI - mild changes in memory and other cognitive abilities; these changes can be detected through careful evaluation, but do not interfere with day-to-day activities.  Dementia - changes in two or more aspects of cognition and behaviour that interfere with function in everyday life. Alzheimer’s & Dementia 7 (2011) 257–262 79
  • 80. DIFFERENTIAL DIAGNOSIS  Dementias of other types  Delirium  Depression  Schizophrenia  Normal ageing  Mental retardation 80
  • 81. S.N Pseudodementia Dementia 1 Informant aware of memory disturbance and can date the onset accurately Onset is insidious and informant usually can not date onset. 2 Patient complains enthusiastically about the memory loss Unlikely 3 Questions about cognitive functions lead to DON’T KNOW RESPONSE accompanied by irritation Try their best but are incorrect 4 History is usually short and often there is a previous history of depressive episode History is long and depressive episode may or may not be present 5 Depressed patients perform better on memory tests. Don’t perform well. 6 Memory complains are accompanied by insomnia, diurnal variation etc. May or may not be present 81
  • 82. Feature Dementia Delirium Onset Insidious Sudden Duration Months to years Hours to week Attention Preserved Fluctuates Memory Impaired Impaired recent and immediate Speech Word finding difficulty Incoherent Sleep & wake cycle Fragmented sleep Disrupted sleep, day night reversal Thoughts Impoverished Disorganized Awareness Unchanged Reduced Alertness Usually normal Hypervigilant or reduced vigilance 82
  • 83. 83 Characteristics Alzheimer’s Disease Vascular Dementia Sex Women Men Age Generally over age 75 years Generally over age 60 years Onset & progression Gradually progressive Episodic with stepwise deterioration History of hypertension Less common Common History of stroke(s),transient ischemic attack(s),or other focal neurological symptoms Less common Common Hypertension Less common Common Focal neurological signs Uncommon Common Emotional lability Less common More common Cognitive deficits Uniform patchy
  • 84. Features Pick’s disease AD Personality change Early Late Amnesia Late Early Language disturbances Early Late Stereotypes Early Mid or late Apraxia, agnosia, alexia Late Variable Kluver-Bucy syndrome Early Late Visuospatial disorientation Rare Common Age of risk Mean 50, up to 80yrs Risk increases with age CT Scan Fronto-Temporal atrophy Widespread atrophy Gross Pathology Anterior hemi. Atrophy, Posterior hemispheric atrophy, Histopathology pick’s body Neurofibrillary tangle 84
  • 86. MANAGMENT  Treatment of AD  Treatment of secondary symptoms  Experimental therapy  Preventive measures 86
  • 87. Treatment of AD  Cholineesterase inhibitors - mild-moderate AD  Donepezil  Rivastigmine  Galantamine  NMDA antagonists – severe AD  Memantine 87
  • 88. 88 Characteristic DONEPAZIL RIVASTIGMINE GALANTAMINE MEMANTINE Chemical class Piperidine Carbamate Phenanthrene alkaloid Similar to amantadine Primary mechanism AchE inh AchE inh AchE inh NMDA antagonist Other mechanism None BuchE IN Nicotine modulator HT3 receptor antagonist Half life 70 h 90 min 7 h 70 h Metabolism Hepatic Renal Hepatic Hepatic
  • 89. Current status of AChE Inhibitors  Treatment over 6 month produce improvement in cognitive function.  Benefits were also noted on ADL and behaviour.  Direct comparison – equivocal result.  Delay institutionalization  Decrease troublesome behaviours  Combining memantine with AChE inhibitors - slowed cognitive and functional decline. 89
  • 90. 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 90
  • 91. TREATMENT OF SECONDARY SYMPTOMS  Neuroleptic agents  FDA in 2005 black box warning for atypical neuroleptics  2008 - haloperidol, chlorpromazine and thioridazine included  Typical antipsychotics – cardiac arrythmia and EPS  Atypical – thromboembolism and aspirational pnemonia.  Cognitive decline with both 91
  • 92.  Antidepressants  Sertaline & fluvoxetine – no benefits (wintraub & petrecca et al study)  Mirtazipine has no benefial effect ( Banerjee et al)  Recommendation – not effective – not recommended.  Anticonvulsants  Very limited evidence to support use 92
  • 94. 94  To date there is no effective approach in terms of cure or prevention of dementia.  The available pharmacological therapy is largely symptomatic, with temporary clinical benefits on cognitive, functional and behavioural manifestations of the disease.  There is an urgent need to develop new drugs with disease-modifying properties for AD.
  • 95. 95  A disease-modifying drug is a agent intended to slow the progression of the neurodegenerative process by inhibiting critical events in the pathophysiology of the disease.  Patients treated with such agents would be expected to have a more benign course of the disease when compared to placebo-treated individuals
  • 96. 96  Many drugs have been proposed and tested in neurobiological models of AD.  However, the promising effects of these compounds in animal models failed to prove beneficial to humans.  In addition, other drugs that underwent clinical experimentation delivered negative results, either due to limited efficacy or toxicity.
  • 97. 97
  • 98. 98
  • 99. Therapeutic targets for disease modification in AD 99  More than 200 pharmaceutical compounds are currently undergoing phase 2 and 3 trials.  Grossly divided into :  Anti amyloid  Drug that target other pathways
  • 100. Anti-amyloid compound 100 1. Block/inhibit the overproduction or aggregation  Gamma secretase inhibitors  Beta secretase inhibitors 2. Favour its clearance from the brain  Active immunisation  Passive immunisation
  • 101. 101
  • 102. 102
  • 103. ACTIVE IMMUNIZATION 103  Induces an IgM response to generate antibodies against pathogenic Aβ, which further mobilize microglia to clean plaques through phagocytosis  AN 1792 – PHASE 2  The trial was interrupted due to the occurrence of meningoencephalitis in 6% of subjects.  CAD106 - PHASE 1  Able to reduce Aβ accumulation in cortical and subcortical brain regions Bioorg Med Chem Lett 2011; 21 : 2655-8. S, Jacobson LH, et al.. J Neurosci 2011; 31 : 9323-31.
  • 104. PASSIVE IMMUNISATION 104  Intravenous administration of full monoclonal antibodies or antibody fragments which directly target Aβ.  BAPINEUZUMAB  Undergoing phase 3 studies.  Researchers reported that it failed to protect against cognitive and functional decline of AD patients undergoing a phase 3 trial. Neurology 2009; 73 : 2061-70.
  • 105. 105  SOLANEZUMAB  Phase 3 trials failed to demonstrate clinical benefits.  But In a study conducted in Japan with AD patients associated with increased clearance of Aβ from the brain.  PONEZUMAB  Targets the amino-terminal portion of Aβ1-40  Phase 2 studies did not confirm clinical efficacy. The European Federation of Neurological Societies annual 23. meeting, in Stokholm, Sweden; 2012. Clin Neuropharmacol 2013; 36 : 14-23.
  • 106. Inhibitor of production and accumulation of Aβ 106  γ-secretase inhibitors  Semagacestat –  Phase III trials found no efficacy.  Even it was associated with increasing cognitive impairment and worsening daily living activities, as well with increasing risk for skin cancer.  Avagacestat –  Inhibitor of Ab 40 and Ab 42 formation  Phase 2 study
  • 107. Tau-oriented strategies 107  LITHIUM AND VALPROATE - Inhibit GSK – prevent Tau phosphorylation in animal models  Valproate was not associated with reduction of cognitive or functional decline.  Long-term lithium treatment was associated with stabilization of cognitive and functional parameters, in addition to a reduction in CSF concentrations of phosphorylated Tau.  Phase 2 study in patients with mild AD treated with lithium for a shorter (10 wk) period, no significant differences were observed in biological or clinical outcomes. Neurology 2011; 77 : 1263-71. J Clin Psychiatry 2009; 70 : 922-31 Br J Psychiatry 2011; 198 : 351-6.
  • 108. 108
  • 109. Others 109  Ginkgo biloba  Previously - effective in mild to moderate Alzheimer’s disease with an advantage over placebo.  Recent cochrane review – no evidence of efficacy  Several reports of bleeding. Pharmacopsychiatry 2003; 36:297–303. Cochrane Database Syst Rev 2009; 1:CD003120
  • 110. Antibiotics  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 110
  • 111.  Standardized ADAS Cog significant @ 6 but not 12 months  Standardized MMSE score higher @12 (but not 3 or 6) months  Intriguing results!  Larger study in planning stages Loeb M, Molloy DW et al JAGS 2004;52:381 111
  • 112.  vitamin E  High dose Vit E (2000U/day) for 2 yr slowed progression of AD ( large double blind placebo trial ,Sano et al 1997)  Alzheimer Disease Cooperative Study ( 769 pts) showed no benefit vs placebo (Peterson et al 2005)  Cause cardiovascular side effects  Not recommended currently 112 Cochrane Database Syst Rev 2008; 3:CD002854.
  • 113.  Estrogen replacement therapy  RCT with 351 pts for 2 weeks showed no beneficial effects  Cholesterol lowering agents  RCT, double blinded study with 748 pts for 6 months failed to prove efficacy 113 McGuinness B et al. Statins for the treatment of dementia. Cochrane Database Syst Rev 2010; 8:CD007514.
  • 114.  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. 114
  • 115. 115  Omega-3 supplementation  174 patients in a placebo-controlled RCT  No significant overall effects on neuropsychiatric symptoms, on ADL or on caregiver’s burden  Positive effects were seen on depressive symptoms Freund-Levi Y et al. Int J Geriatr Psychiatry 2008; 23:161–169.
  • 116. 116  Dimebon (latrepirdine)  Non-selective antihistamine previously approved in Russia  Weak inhibitor of BuchE and AchE , weakly blocks the NMDA receptor signalling pathway.  A company sponsored study completed in Russia included 183 patients - significant benefits compared with placebo.  In the recent CONNECTION study, dimebon was not more effective than placebo. Doody RS et al. Lancet 2008; 372:207–215.
  • 117. 117  Huperzine A  Alkaloid isolated from the Chinese herb Huperzia serrata  AChE inhibitor used since 1994 in China.  A recent meta-analysis found that huperzine A 300–500 g daily for 8–24 weeks in Alzheimer’s disease led to significant improvements in MMSE and ADL. Wang BS et al. J Neural Transm 2009; 116:457–465.
  • 118. 118  Cerebrolysin  Porcine brain-derived peptide  Cerebrolysin was superior to placebo in improving global outcome measures and cognitive ability in several RCTs of up to 28 weeks.  A large RCT comparing cerebrolysin, donepezil or combination therapy showed beneficial effects on global measures and cognition for all three treatment groups compared with baseline. Plosker GL et al. Spotlight on cerebrolysin in dementia. CNS Drugs 2010; 24:263–266.
  • 119. STEM CELL THERAPY  South Florida university  Mouse model study in 2009  Several infusions of stem cells from umblical cord  Myeloid protein reduced by 62%  Cerebral amyloid angiopathy reduced by 82%  Hope to begin human trials. 119
  • 120. Conclusions 120  Most phase 3 trials with candidate drugs for AD in the last decade failed to present unequivocal clinical benefits, or were suspended due to severe adverse events.  To date, treatment of AD relies on the symptomatic effects of cholinesterase inhibitors and NMDA-receptor antagonists.
  • 121. Preventive measures 121  Exercise regularly  Eat a healthy diet rich in fruits and vegetables  Engage in social and intellectually stimulating activities  Control type 2 diabetes  Lower high blood pressure levels
  • 122. 122  Lower high blood cholesterol levels  Maintain a healthy weight  Stop smoking  Get treatment for depression