Professional Documents
Culture Documents
By
Prof. K.YELLAMMA
Professor (Rtd)
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Statistics of Alzheimer’s Disease
• 1 in 8 persons at the age > 65
• Lifetime risk: Women > men
• One among top 10 leading causes of death for all ages.
• 6th leading cause of death in U.S. 2009, 7th leading cause of
death in world
• Scientists estimate that around 5.3 million people now have AD.
• In people over 65 years, the percentage of people with AD
doubles for every 5 years.
• By 2050, 13.2 million older Americans are expected to have AD
if the current numbers hold and no preventive treatments become
available.
• The national cost of caring for people with AD is about $100
billion every year.
Postal stamp of US Govt WHO-AD Associations(71)
•Symptoms :
Memory loss, language problems,
and unpredictable behavior.
The neurons in the neocortex,
hippocampus, amygdala, and the
basal forebrain cholinergic system
are the most affected brain regions
• Auguste had died after several years of progressive mental
disorientation characterized by confusion and memory loss.
• In her cerebral cortex, the part of brain responsible for reasoning and
memory, he found strange bundles of nerves, which he termed
Neurofibrillary Tangles and accumulations of cellular debris around
the nerves, which he termed Senile Plaques.
CAUSES FOR AD
• Following are the different causes of AD:
• AGE
• FAMILY HISTORY
• HERIDITARY FACTORS
• DOWN’S SYNDROME
• WHIPLASH OR HEAD INJURIES
• ALUMINIUM
• POOR EDUCATION
• CONSUMPTION OF HIGH FAT, HIGH
CALORIFIC DIET
• PREVIOUS SERIOUS TRAUMA TO THE
HEAD
• SMOKING
• CARDIOVASCULAR DISORDERS
• HYPER CHOLESTEROLEMIA
• DIABETES MELLITUS
• MENOPAUSE AND
• SEDENTARY LIFE STYLE
TYPES OF AD
• Adults with Down’s syndrome are often in their mid to late 40s or
early 50s when symptoms appeared
• Strikes almost half of all the people over the age of 85, may or may
not be hereditary.
• Personality changes
• Bedridden
• Incontinent and
Bronchopneumonia
Urinary infection or
Aspiration.
Genetics of Alzheimer's Disease
E2 ---------> Protective
E3 ---------> most common form of gene
E4 ---------> confers an increased risk of AD
Genetic and Environmental Factors in Alzheimer’s Disease
Genes Environment
-amyloid precursor Head trauma
Presenilin – 1 Alzheimer’s Vascular factors
Presenilin – 2 HSV-1
APOE-E 4 Disease Total cholesterol
Hypertension
Protective
N.S.A.I.D.’s
Prednisone
Vitamin-C
Estrogen
APP APOE Tau Alpha-2- Clusterin
macroglobulin
• Cholinergic hypothesis:
The oldest, on which most currently available drug therapies are based is the
cholinergic hypothesis, which highlights that Alzheimer’s Disease is cuased by
reduced synthesis of the neurotransmitter, Acetylcholine. The most prominent
changes occur is the loss of cholinergic neurons in the basal forebrain that
project to the hippocampus and neocortex, which play an important role in
memory and cognitive function. The loss of cholinergic neurons results in
upto a 90% reduction in the activity of acetyltransferase, which is needed for
the synthesis of acetylcholine.
• Amyloid hypothesis:
This hypothesis, substantiates that Amyloid beta (ABeta) deposites are the
causative factor in the disease (Mudher and Lovestone, 2002).
• Tau hypothesis:
An extensive research investigation by Schmitz et al.,(2004) demonstrated
that hyperphosporylated tau begins to pair with other threads of tau and they
tangled up together inside nerve cell dodies in masses known as neuro
fibrillary tangles ( Goedert et al., 1991) eventually leading to disintegration
of microtubules and collapsing of the neuron’s transport system (Iqbal et al.,
2005).
NEUROCHEMICAL CHANGES
• The initial findings were reported by Bowen et al., 1976 who found a marked
loss of basal forebrain cholinergic neurons and also large reduction in
cholinergic markers such as the cortex, hippocampus and amygdala.
• In the cortex, there is some loss of both presynaptic and post synaptic
serotonergic markers.
• The last 15–20 years have seen a wealth of studies to characterize the
neurochemical abnormalities of Alzheimer's disease, in particular
those involving the β-amyloid and tau proteins, as well as more
recently, apolipoprotein E4.
AD patients show high Tyr nitration in both neurons and glial cells
•They are abundant in Neurons in the CNS & less in else where.
•The PSEN1 gene has multiple transcriptional variants and its functions
could include the cleavage of APP and notch receptor
protein .
•PSEN1 located on Chromosome 14.
•The PSEN2 gene has two transcriptional variants and its functions could
include the cleavage of APP and notch receptor protein
•PSEN1 located on Chromosome 1.
•Dominant mutations in the genes that encode presenilin proteins are the
most common cause of familial early-onset Alzheimer's Disease
Nicastrin precursor
Normal Advanced AD
Identification of AD
Diagnostic Criteria
• Cognitive impairment severe enough to cause social or occupational
disability in at least two domains
– Memory
– Language
– Calculations
– Orientation
– Judgment
Treatments
– Acetylcholinesterase inhibitors
– Anti-amyloid vaccine?
– Detoxification of β-amyloid?
– Vitamin E intake
• There was no cure for Alzheimer’s Disease; available treatments offer relatively small
symptomatic benefit. Current treatments can be divided into
• pharmaceutical, psychosocial and caregiving.
• Pharmaceutical: The following drugs are variously used for the treatment of Alzheimer’s
Disease
• Cholinergic Therapy of Possible Benefit in the Treatment of Alzheimer's Disease
• Breaks acetylcholine
• Promotes aggregation of β-amyloid
O H
+H2O O N+ -
O
+
O N+ HO N+
O
O
O
acetylcholine H
tetrahedral intermediate choline acetate
AchE Inhibitors
Donepezil
Tacrine
(Aricept) O (Cognex)
H
Cl H2
C O Cl
NH2
H H
N
O
C
H2
H CH3
N
O CH3
Rivastigmine
Galantamine
Acetylcholine (Exelon)
(Reminyl) O
HO
H O N+
H O N
O O
C4H6O6
O
Br
N
NH
CH3
NMDA
Receptor
Antagonist
• Memantine/Auxura/Namenda
• Regulates Calcium influx
• Replaces Magnesium Ions
• Chelates copper and zinc in vitro
• Treatment reversed the deposition of amyloid in the brains of mice with AD
• Clioquinol cut amyloid deposits in half over a nine week period with no
adverse effects. Cl
N I
OH
• Vitamin E (2000 IU/d) and selegiline (10 mg/d) have been shown to reduce
the rate of decline of functions in patients with AD.
– Combined therapy was not superior to either agent alone.
• Evidence to support the use of other antioxidants, anti-inflammatory agents,
or herbal medications such as ginkgo biloba is insufficient to recommend
use as standard therapies.
• Estrogen in standard doses has been shown not to improve cognition in
postmenopausal women with AD
FUTURE HOPE
• Reducing amyloid production, aggregation or enhancing its removal are
promising avenues of treatment that will address the basic pathophysiology
of AD.
• Epidemiologic data suggest that some agents may decrease the likelihood
of developing AD.
– nonsteroidal anti-inflammatory agents
– hormonal treatments
– histamine H2 blockers
– antihypertensive agents
– statins
• Spouses – the largest group. Most are older with their own
health problems.
• Daughters – the second largest group. Called the “sandwich
generation,” many are married and raising children of their
own. Children may need extra support if a parent’s attention
is focused on caregiving.
• Grandchildren – may become major helpers.
Primary Secondary
Prevention Prevention Treatment
Pre- Mild
Normal symptomatic Cognitive AD
AD Impairment
No Disease, Early Brain Mild Memory Mild, Moderate
No Symptoms Changes, Loss and Severe
No Symptoms Impairment
Disease Progression
PREVENTION
• Intellectual activities such as playing chess or regular social interaction have
been linked to a reduced risk of AD.
• The components of mediterranean diet, which include fruit and vegetables, bread,
wheat and other cereals, olive oil, fish and red wine, may all individually or
together reduce the risk and course of AD.
• Curcumin from the curry spice turmeric has shown some effectiveness in
preventing brain damage in mouse models due to anti-inflammatory properties.
• A 21- year study found that coffee drinkers of 3-5 cups day at midlife had a 65%
reduction in risk of dementia in late life.
NIA_Alzheimers_640_Video.vob.wmv
NIA_Alzheimers_640_Video.vob.wmv
ACKNOWLEDGEMENTS
THANK YOU