Download Alzheimer`s Disease

Alzheimer’s Disease
A progressive neurodegenerative
disease first characterised by
Alios Alzheimer, Germany 1906
Alois Alzheimer 1906 wrote….
• “A woman (Frau Auguste D) exhibited ideas of jealousy against her
husband, rapidly progressing loss of memory, inability to find her
way around the home, dragged objects back and forth, hid them; at
times she believed that someone wanted to kill her and began to
shout loudly”.
• Frau Auguste D died aged 51 in a local mental asylum following a
number of years of progressive dementia.
• Alzheimer carried out microscopic examination of her brain tissue.
He observed:
– structures previously described in the brains of elderly people – neuritic
or senile plaques
– structures contained within brain cells that had not been previously
observed – neurofibrillary tangles.
• Both of these microscopic changes are used to characterise the
form of dementia known as Alzheimer’s Disease (AD)
AD – Brief history of diagnostic criteria
• In the early part of the 20th Century a positive diagnosis of AD was:
“a person with dementia who was less than 65 years old”.
• In individuals “senile dementia” was assumed to be vascular
disease associated with old age.
• During 1962 – 1970 studies showed that neuronal cellular
inclusions, plaques and tangles were present in older individuals in
the absence of vascular degeneration.
• Recognised that AD could not be restricted to under 65s. The term
Alzheimer’s Disease now describes dementia of the Alzheimer type
irrespective of the age of onset.
• A definite diagnosis requires demonstration of the presence of
plaques and tangles – post mortem microscopic analysis
• Prior to death, the diagnosis is “probably AD” if the patient has a
history of progressive dementia-but new scans enable more certain
diagnosis.
Alzheimer’s Disease-Background
• Alzheimer's Disease (AD)
is most commonly
diagnosed in older age
groups (65+)
• Currently estimated that
there are 400,000+ AD
sufferers in the UK
• Death often occurs 5-10
years after diagnosis.
• Sufferers include Ronald
Regan, Charlton Heston
Maggie Thatcher, Terry
Pratchett Iris Murdoch.
Alzheimer’s Disease-Background
Broad clinical characteristics of AD
• Symptoms
–
–
–
–
Memory lapses of increasing frequency and extent
Problems with word finding
Disturbed/repetitive behaviour
Effects on social function
• Confusion, disorientation
• Lack of memory affects organisational skills
• Mood swings-depression, anger, paranoia
• Loss of confidence, withdrawal
• Loss of life skills and independence
“Typical” steps of progression
Not AD –other dementia?
Mild Cognitive
Impairment
Not AD but may
represent AD risk
AD early phase. Forgetfulness,
Anxiety/agitation, paranoia,
disorientation.
Middle phase. Anomia, aphasia,
Withdrawal, loss of insight
Fretful purposeless activity.
Late phase. Aphasia, affected
comprehension. Disorientation in
time and space. Psychiatric symptoms
Need for care for all daily activities
Alzheimer’s Disease - clinical
• AD is the most common dementia (accounts for 6080% of dementia in elderly)
• 5-10% >65yr affected (up to 45% >85yr)
• Slow, progressive – 5-10yrs
• Complex presentation and progression
• Becoming a major health burden as population ages
CNS damage correlates with symptoms
• Changes most prominent in:
•
•
•
•
Hippocampus
Entorhinal cortex
Association cortex
Basal forebrain
• Accounts for early signs
– memory loss + disturbance of higher cortical
functions
– preservation of primary sensory/motor functions until
later
Indicative sites of key brain areas – not all visible in this cross-section
Part of
association
cortex
Entorhinal cortex
Hippocampus
Basal forebrain nuclei
PET Scan
Normal
Positron emission tomography
Alzheimer’s
Radiolabelled 2-deoxyglucose
Development of AD pathology
• Gradual onset
• Accumulation of neuronal pathology
– Protein build up
– Neuronal loss
• Compensation ability of CNS overwhelmed
• Clinical symptoms of AD
• Continued pathology and symptom development
Main pathology
Generation of inclusion bodies
Molecules Central to Pathology
• Proteins/peptides
• Amyloid b-peptide
• Presenilins
• Apolipoprotein E
• tau: microtubule-associated
Protein accumulation pathology
Alzheimer’s disease - Pathology
• Extracellular plaques (Amyloid plaques)
• Cerebral cortex
• Cerebral/meningeal blood vessel wall
• Plaques
• Dense amyloid core
• Dystrophic neurites + reactive glia surround
• Intraneuronal neurofibrillary tangles
(Tau protein fibrils)
•
•
•
•
Neuronal + synaptic loss
Reactive astrocytosis
Microglia proliferation
Later inflammation
• Pathology correlation with dementia
• Plaque no. – some correlation
• Tangles no. – more correlation
Examples of Cellular Inclusions
B. Tau Protein in Alzheimer's
Disease
C. a-Synuclein in Parkinson’s
Disease
Diffuse plaque
• Amyloid b protein
deposit (A b1-42)
• Non-aggregated
(fibrillar) form
• Intact neurones within
plaque boundaries
Neuritic plaques
• Develop from diffuse/immature plaques
• Spherical areas, 10-150nm diameter
• Foci of enlarged axons, synaptic terminals,
dendrites
– Associated with extracellular b-amyloid
– Dystrophic neurites within plaque – tau accumulation
– Proliferating astrocytes/microglia surround
AD - Neurofibrillary tangle
Neurofibrillary tangles
• Major pathological feature
• Brain area affected correlates with severity of
dementia
• Flame shaped or globoid intracellular inclusions
• Persists as extraneuronal structure – “ghost”
• May represent cell damage by impaired
intracellular transport systems
Neurofibrillary tangles
Tangles thought to comprise isoforms of Tau
proteins
• Paired helical fibrils (insoluble) and PHFs
soluble straight filaments (SSfs)
• Abnormally (hyper)phosphorylated microtubuleassociated protein tau = subunit of PHF
• PHFs found also in dystrophic neurites.
b – Amyloid
• Cause or an effect of AD?
(protein misfolding?)
• Neuritic plaque major protein (70%)
– Toxic to cultured neurons
• Amyloid deposits aggregates of Ab containing 40
or 42 residues - insoluble
• Ab40 normally produced in small amounts
• Ab 42 overproduced due to genetic mutations
(ADP transcripts found in AD brains)
Presenilins
• Presenilin 1 linked with 70% familial
cases
• 7 transmembrane protein,
• Presenilin 2 linked with 20% familial
cases
• 67% similarity
• Expressed in neurons – ER/golgi apparatus
• Processing/transport role for proteins
Tau Protein
• Microtubule-associated protein
• Abnormal concentration in neuron cell bodies
• Normally synthesised in the body and
transported to the axon in high concentrations
Pathogenesis of AD
[From Rang et al ‘Pharmacology’ 5th Ed]
Genetics
APP: chrom 21q21.
>23 mutations
PSEN1: chrom
14q24.3
PSEN2: 1q42.1
APOE4: epsilon 4
isoform
+ others
= genetically
complex disorder
Potential protein manufacture control route
Neurochemical changes in AD
• Changes in many transmitter systems
• Relatively selective loss of cholinergic neurons
(ACh releasing)
– Choline acetyltransferase activity in
cortex/hippocampus reduced (30-70%)
– Acetylcholinesterase activity reduced
– Muscarinic R density unaffected
– Nicotinic R reduced (cortex particularly)
• Excess glutamate? Excitotoxicity
Treatment
• No current treatment can arrest AD
• Some treatments can slow progress
• Cholinesterase inhibitors (Tacrine, Donepezil,
Rivastigmine, Galantamine)
• Memantine
• Other medicines can help control behavioural symptoms
– sleeplessness, anxiety, depression
• Novel targets – protein construction
Drug therapy (1)
• No real therapy until the mid 1970s when it was observed that the
activity of the enzyme responsible for synthesising ACh was
reduced in the cerebral cortex of AD patients.
• Hypothesis that AD was a consequence of dysfunction of cholinergic
neurones.
• Attempts to increase cholinergic function by increasing dietary
choline not appropriate results patients smelling of rotting fish!
• Introduction of AChE inhibitors which work by prolonging the half-life
of ACh in synaptic clefts – first drug used was tacrine
Cholinesterase inhibitors
• Mild to moderate AD
• Delay or prevent
worsening for limited
time
• Prevent breakdown of
ACh
• Cholinergic neurons
damaged and lost linked to memory loss
Presynaptic
neuron
Stag
e1
Stage 2
Stage 3
Stage 5
ACh
Stage 4
Stage 9
X
astrocyte AChE ACh
Postsynaptic neuron
Drug therapy (2)
Second generation AChE inhibitors with less side effects were
developed – donepezil, rivastigmine and galantamine
• AChE inhibitors modest effects- some patients showing no obvious
benefit. Anticholinersterases treat mild to moderate AD
Attempts to activate ACh receptors more directly using ACh agonists:
– Nicotine shown to improve attention span in AD patients
– Nicotinic agonist ABT-418 has cognitive-enhancing properties
• Muscarinic antagonists such as atropine have been shown to induce
memory loss in humans.
• Potent muscarinic agonists (e.g.arecoline, oxotremorine and
pilocarpine) have too many side effects to be useful but have been
shown to improve memory in some patients & animal models.
Drug therapy (3)
• Muscarinic autoreceptors have been shown to control the release of
ACh and attempts have been made to develop specific antagonists
to these presynaptic cholinergic autoreceptors.
• One such molecule, AF-DX-116 has been shown to improve
cognitive performance in experimental animals while SCH-217443
has shown efficacy in increasing ACh release .
• …but alvameline, a combined muscarinic agonist and antagonist potential treatment for AD phase II/III trials failed to demonstrate
therapeutic efficacy.
• Glutamate NMDA receptors also play a role in cognitive function and
neurodegeneration and the NMDA antagonist memantine was
launched in 2002 as the only treatment for moderate to severe AD (
NMDA Receptor Antagonist
•
•
•
•
•
N-methyl-D-aspartate receptor is normally activated by glutamate
Excess glutamate can be detrimental and lead to cell death
Memantine (Namenda) dampens glutamate effects via NMDA R
Allows physiological NMDA R activities to continue
Can be given with cholinesterase inhibitors
Dissolving amyloids?
HSP 104
Education – a risk factor?
• BBC report 16 Feb 06
• High levels of education may
help people to better resist AD
initially.
• However once accumulated
damage reaches a critical
level, decline inevitable and
swift.
• Whether truly related to
schooling or associated
factors (wealth/
occupation/lifestyle) yet to be
determined.
http://news.bbc.co.uk/1/hi/
health/4713570.stm
Exercise 'cuts Alzheimer's risk'
BBC report: January 2006
• Regular exercise
reduces the risk of
dementia and
Alzheimer's disease by
up to 40%. (US
research).
http://news.bbc.co.uk/1/hi/h
ealth/4616502.stm
Common agents and AD
• Aspirin (NSAID)
– Evidence that decreases risk and slows onset
of AD
• HRT
– Unconfirmed observation that reduces
incidence or slows onset in women
• Nicotine
– Controversial suggestion that it protects
against AD (as for PD)
Are we accurately presented with
the Facts by the Media?
How is this
figure
potentially
misleading?