Download Dementia - ISpatula

Mayyada Wazaify, PhD
Alzheimer’s disease (AD)
• A gradually progressive dementia affecting
cognition, behavior & functional status.
• Drugs may reduce AD symptoms, but disease
is eventually fatal.
• Need for supervision & assistance increases
until patients become totally dependent on
family member, spouse, or other caregiver for
all of their basic needs.
Dementia
• A syndrome, the most prominent feature of
which is impaired short-term and long term
memory
• The 5th leading cause of death in the US.
• The majority of individuals with dementias
suffer from primary degenerative dementia
(i.e. Alzheimer’s= 50%)
Other types of dementia:
• Vascular dementias VaDs (including multi-infarct
dementias and Binswanger’s disease)
• dementia with Lewy bodies (DLB),
• Parkinson disease with dementia (PDD)
• Frontotemporal dementia
• Pseudomenetia
Dementia vs. Amnesia?
• Dementia is not a disease but a series of
symptoms that leads to serious mental
diseases.
• Amnesia on the other hand, is a serious
mental condition affecting a person's memory.
Symptoms of dementia could affect a person's
memory. But it generally affects a person's
decision making.
Prevalence of dementia
• Ranged 2.5% in GB to 24.6% in the former
Sovient Union.
• US studies: 3.5%-16.1% in people = or >65
• US- AD 10% in those = or > 65
• Worldwide AD prevelance= 1%
• AD: 2.3 million Americans
Clinical Presentation
• Dementia is a syndrome that exhibits impaired
short- and long term memory (most prominent feature)
• Multiple cognitive deficits that compromise
normal social or occupational function
• Commonly, forgetfulness is the primary
complaint of patients or the first symptom
noted by the family.
Apraxia
Agnosia
Instrumental Activities of
Daily Living (IADL’s)
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Telephone
Travel
Shopping
Meals
Housework
Medicine
Money
Basic Activities of Daily Living (ADL)
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Bathing
Dressing
Grooming
Toileting
Continence
Transferring
Alzheimer’s Disease
• A gradually progressive dementia affecting
cognition, behavior & functional status.
• A definitive cause for AD has yet to be
determined.
• ?? Aluminum toxicity, young or old maternal
age, small head circumference and brain size
and low intelligence
• Genetics play a significant role in the
development of Alzheimer-type dementia
Genetics and AD
• First degree: 24%-64%
• ↑ in families with Down syndrome or other
defects to chromosome 21
• AD affects virtually all Down syndrome
patients who survive into old age
• Abnormalities in serum proteins and immune
function: APP  (β-amyloid) subunit– esp.
early onset AD
Genetics and AD
• Apolipoprotein E (ApoE) plays a role in the
development of sporadic, late-onset AD.
• Amyloid protein can commonly be found in the neuritic
plaques, which occur in Alzheimer-type dementia;
• Amyloid protein is also noted in blood vessel walls of
patients with AD.
• β-Amyloid protein deposits occur early in the course of
Alzheimer dementia and are distinct from the amyloid
proteins found in other amyloid disorders, such as
primary amyloidosis or multiple myeloma.
Neuropathology of AD
Neuro Degenerative
neuron
loss
2 Major Players:
1. Plaques (outside cells)
2. Tangles (inside cells)
Gyri: “narrower”
Sulci: “wider”
Ventricles:
“larger”
Atrophic hippocampus in AD
MRI Scan of Patient with AD
• Brains of AD patients
show considerable
atrophy
– Greatest atrophy seen in
anterior frontal &
temporoparietal regions
(sparing of occipital & primary motor
& somatosensory cortices)
Histology
• Granulovauolar degeneration is the major
histologic findings in AD
• The loss of cortical neurons that originate in the
nucleus basalis and project into the cerebral
cortex is the most significant histopathological
consequence of AD
• Cell loss, granulovacuolar degeneration, and
neurons with NFTs are concentrated in this area
Neurotransmitter changes
• ↓ Choline acetyltransferase by 60% to 90% in
the cortical and hippocampal regions.
• ACh+ AChE are also ↓
• Muscarinic- normal or moderate ↓
• Nicotinic receptor proteins- ↓
• NE, serotonin and GABA- normal or moderate ↓
• Somatostatin and CRF are also reduced
BRAIN VASCULAR DISEASE
AND HIGH CHOLESTEROL
• A growing evidence CVD & risk factors  incidence of
AD.
• Apo E: synthesized in liver, CNS & CSF
• Responsible for transporting cholesterol in blood
through brain.
• It is carried by LDL into neurons binds to NFTs.
• Apo E4 is associated with increasing deposition of βamyloid and  accelerating modulator in course of
vascular dementia.
OTHER MECHANISMS
1. oxidative stress,
• vitamin E, & possibly combination with vitamin C, may prevent AD
2. Mitochondrial dysfunction,
3. postmenopausal loss of estrogen in women.
• extent of contribution is uncertain.
• Estrogen:
1. may be important in maintaining normal cholinergic
neurotransmission.
2. may increase NMDA receptor numbers in brain areas involved in
recording new memories & prevent cell damage by acting as
antioxidant.
3. estrogen increases cerebral blood flow & glucose use,
4. reduces plasma levels of Apo E,
5. blunts stress-related glucocorticoid release.
Screening for Dementia
• Initial Test: Folstein Mini-Mental Status Exam
(MMSE): orientation, registration, attention and
calculation, recall, and language
• The Blessed Dementia Scale evaluates daily
functional capacity (e.g., shopping, performing household tasks),
ADL (e.g., eating, dressing, toileting), and personality.
• The Blessed Information-Memory-Concentration
Test evaluates orientation, memory, and
Clock Drawing Test (CDT)
TREATMENT OF ALZHEIMER
DISEASE
Non-Pharmacologic
Non-Pharmacologic
Basic Principles:
• Maintaining independence as long as possible
• Keeping patients in familiar surroundings
• Avoid confrontation. Remain calm, firm, & supportive if the
patient becomes upset
• Provide frequent reminders, explanations & orientation cues.
• Employ guiding, demonstration, & reinforcement.
• Reduce choices, keep requests & demands of patient simple, &
avoid complex tasks that lead to frustration
• Personal discomfort may also trigger behaviors, so it is
important to monitor for pain, hunger, thirst, constipation, full
bladder, fatigue, infections & skin irritation, comfortable
temperature, fears, & frustrations.
Pharmacologic Treatment
5. Role of glutamate on
NMDA receptors
Pharmacologic Treatment
Donepezil
• First of 2nd generation AChE-I
• The only cholinesterase inhibitor currently
indicated for the severe stage of AD
• More selective to Ach-E
• Completely bioavailable
• Long t ½ once daily
• Improves cognition, global function, and
behavioral symptoms across all stages (mild,
moderate, and severe)
Rivastigmine
• Inhibits both AChE and BChE, primarily in CNS
• “pseudoirreversible” inhibitor- WHY?
• It can be dosed twice daily although t1/2 is 1
hour! WHY?
• Absorption is nearly complete, but because of
significant first-pass effect, bioavailability is
approximately 36%
• metabolized via hydrolysis to renally excreted
inactive compounds. (So what?)
• Available as a patch that can be placed daily
Galantamine
• AChE-I + stimulated nicotinitic receptors
distant from Ach sites
• rapidly and completely absorbed, reaches
peak serum levels in <2 hours,
• half-life of approximately 5 hours.
• ER formulation: once daily
• In all AChE-I drugs: A dose titration interval of
4 weeks reduces the severity of adverse
effects and increases tolerability.
NEW
In Jordan
The Glutamate Hypothesis
• Glutamate: predominant excitatory
neurotransmitter in the brain.
• Learning and memory processes in the
hippocampus, for example, are glutamatergic.
• AD is associated with pathologically elevated
glutamate levels within the CNS, which lead to a
high level of ongoing background "noise"
stimulation.
• Pathologic activation of the glutamate receptor
ongoing formation of electrical action potentials
from an influx of calcium into the cell  cell
death
MEMANTINE
• Uncompetitive NMDA receptor antagonist
• It is completely absorbed after oral
administration,
• reaches peak serum concentrations in 3 to 8
hours,
• Its mild voltage dependency and fast-channel
unblocking kinetics preserve physiologic
learning processes without causing intolerable
adverse events
Other investigational Drugs
• Estrogen
• NSAIDs
• MOA-B-Inhibitor (Selegiline)?
• Ginco Biloba