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Manifestation of Novel Social Challenges of the
European Union
in the Teaching Material of
Medical Biotechnology Master’s Programmes
at the University of Pécs and at the University
of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
Manifestation of Novel Social Challenges of the
European Union
in the Teaching Material of
Medical Biotechnology Master’s Programmes
at the University of Pécs and at the University
of Debrecen
Identification number: TÁMOP-4.1.2-08/1/A-2009-0011
Miklós Székely and Gyula Bakó
Molecular and Clinical Basics of Gerontology – Lecture
16
NEUROLOGICAL
DISORDERS IN THE
ELERLY
PART I
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Neurological disorders in
the elderly
Age-related morphological alterations
in the central nervous system
• The weight of the brain decreases
• Protein content of the brain decreases
• Neuron count declines [due to agerelated decline in trophic factors such
as vascular-endothelial growth factor
(VEGF), brain-derived neurotrophic
factor (BDNF), insulin-like growth
factor-1 (IGF-1)]
• The amount of neurotransmitters
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Neurological disorders in
the elderly
Age-related functional alterations in
the central nervous system
• Impaired motor functions, declining
coordination
• Difficulties in spatial orientation
• Walking speed becomes slower
• Impaired postural reflexes, loss of
balance develops easier
• Sleep disorders develop frequently
(superficial sleep)
• Episodic and short-term memory is
especially impaired in normal aging
The most common agingassociated neurological
disorders (outline)
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• Disorders of cerebral blood flow
(stroke)
• Neurodegenerative diseases affecting
motor (and later cognitive) (e.g.
Parkinson’s disease)
• Other, more frequent neurological
disorders also present in old
individuals with high prevalence:
- myasthenia gravis
- Headache
- dizziness (vertigo) in the elderly
The most common agingassociated neurological
disorders (outline)
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• Disorders of cerebral blood flow
(stroke)
• Neurodegenerative diseases affecting
motor and cognitive functions
(Parkinson’s disease and Alzheimer’s
disease)
• Other, more frequent neurological
disorders also present in old
individuals with high prevalence:
- myasthenia gravis
- headache
General characteristics of
the cerebral blood flow
(CBF) I
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• The brain (1.5 kg) is around 2% of body
weight
• Cerebral blood flow represents 15% of resting
cardiac output
• The brain requires 25% of resting oxygen
consumption
• The brain utilizes 70% of daily glucose
consumption
• CBF exhibits autoregulation: between 60140/160 mmHg mean arterial pressure (a
function of systolic and diastolic blood
pressure taking into consideration the
systolic and diastolic times), CBF remains
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Autoregulation of CBF
CBF (ml/min/100 g)
80
50
20
20
80
100
MAP (mmHg)
140
180
CBF is maintained at an optimal level between 60
mmHg and 140 mmHg mean arterial pressure (MAP) due
General characteristics of
the cerebral blood flow
(CBF) II
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• Monroe-Kelly doctrine: the cranial
compartment is incompressible, any increase
in volume of one of the cranial constituents
must be compensated by a decrease in volume
of another.
• Roy -Sherrington hypothesis: local neuronal
activity is related to regional changes in
both cerebral blood flow and metabolism
(1890).
• Because of lack of energy storage in the
brain, a short cessation of blood flow (1-2
sec) leads to loss of consciousness.
• Within 3-5 min irreversible cortical damage
Alterations of cerebral
blood flow (CBF) in the
elderly
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• Age-related decrease in CBF has been
demonstrated in humans, primates, rodents.
This decrease is regional. It affects
primarily those regions of the brain (e.g.
limbic, association cortex) the function of
which most frequently decline in the course
of aging.
• It may already start in the middle-aged.
• Density of precapillary arterioles and
capillaries decrease. (In healthy aging rats,
the density of arterioles on the cortical
surface was almost 40% lower in senescent
animals than in young adults.)
Disorders of CBF in the
elderly: global cerebral
ischemia
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Causes of global ischemia in the elderly
1 Adams-Stokes syndrome: cardiac arrest due to
failure of stimulus formation and/or conduction
in the heart.
2 Late phase of circulatory shocks. During shock
CBF is maintained until the last phase, when
autoregulation and redistribution of systemic
circulation can no longer ensure minimal CBF.
In case of vascular abnormalities damage is
promoted.
3 Acute severe heart failure or decompensation of
chronic heart failure
In the elderly somewhat diminished efficacy of
autoregulation increases the risk for cerebral
Disorders of cerebral blood
flow in the elderly: focal
cerebral infarction
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Stroke = rapidly developing loss of
brain function(s) due to cerebrovascular
disturbances
• In industrialized countries
cerebrovascular diseases present the
third most frequent cause of death
following coronary heart diseases and
malignant diseases.
Types of stroke
• Ischemic stroke (due to obstruction of
cerebral arteries ) above 80%
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Prevalence of stroke by age
and sex (1999-2002)
14,0
% of population
12,0
Men
Women
12.0
11.5
10,0
8,0
6.6 6.3
6,0
4,0
3.1 3.0
2.1
2,0
0.4 0.3
1.1 0.8
1.2
0,0
20-34
35-44
45-54
55-64
Age (years)
65-74
75+
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Types of focal ischemic
damage
1 Transient ischemic attack (TIA)
Reversible cerebral ischemic episode
with symptoms (e.g. paralysis or
weakening of limbs on one side,
disturbance of speech, asymmetry of
the face) lasting for 5 min to 24 h.
In the background reversible
obstruction of small cerebral vessels
are assumed.
Within 2 years of a TIA, risk of a
permanent stroke is very high!
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Causes of ischemic stroke
1 Atherosclerosis of large vessels
providing perfusion to the brain, e.g.
severe obstruction of the a. carotis
interna or that of a branch of the a.
vertebralis), steal syndrome
2 Local thrombus formation initiated by an
atherosclerotic plaque of an
intracerebral artery, e.g. that of an
a. cerebri media branch
3 Cerebral embolisation
Source: an embolus torn away from a
ventricular mural thrombus (following
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Silent ischemic stroke
1 In 20% of neurologically “healthy”
elderly people and 50% of stroke
patients CT or autopsy reveal signs
of previous infarctions (without prior
characteristic neurological symptoms).
2 With age, incidence of such silent
infarcts increases.
3 Their presence enhance the risk of a
symptomatical stroke by 2-4-times,
especially white matter lesions.
4 They double the risk
for dementia
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Other causes of cerebral
ischemia
Hypertensive encephalopathy
Multiple focal microinfarctions in the brain
Mechanism: During a rapid rise in blood
pressure (above the upper threshold of
autoregulation) hyperperfusion with exudation
occurs in some areas and compensatory ischemia
in others.
Lacunar encephalopathy (e.g. atherosclerosis,
DM)
Due to obstruction of small cerebral arteries
small focal infarctions of up to 15-20 mm
diameter develop
Vasculitis, collagenoses, coagulation disorders
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Mechanisms of ischemic
injury of the brain
Impaired metabolism, deficient ATP production
1 Deficiency of the NA/K ATP-ase function in
ischemia leads to Na and water influx into
the cells (intracellular edema).
2 Intracellular Ca level rises , resulting in
neurotransmitter
(e.g. Glu) release, mitochondrial damage and
other metabolic disorders.
3 Ischemia induces release of and diminishes
the reuptake of excitatory neurotransmitter
glutamate. Oxygen consumption and damage of
the brain is further enhanced.
Free radical production
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Mechanisms of ischemic brain
damage
Acute neurochemical changes after Ischemic Stroke
Vessel occlusion
Thrombolysis /
Mechanical embolectomy
Blood flow reduction
Anaerobic
glycolysis
Lactic acidosis H+
Electrochemical gradient
loss:
Influx of Ca2+, Na+, ClH2O
Efflux of K+
Depolarization
Reverse Na+/Ca2+
exchange
Opening of Ca channels
(VSCC)
2+
Ca
release from
internal
stores
Cytotoxic
Endoplasmic
reticulum
edema
stress
Glucose and O2 deprivation
ATP Depletion/Energy
Failure
Mitochondrial
damage
Decreased Ca2+
buffering
 Ca2+
Oxidative stress
ROS
NO / Peroxynitrite
Lipid peroxidation
Irreversible cell damage
Activation of cell death
Cytoskeletal disruption
Failure of glutamate
homeostasis
 release
 reuptake
EXCITOTOXICITY
Therapeutic and/or
preventive measures in
ischemic brain injury
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Therapeutic measures
Following early diagnosis, reperfusion
(neurosurgical intervention or
thrombolysis) must be initiated as soon
as possible (within 2-12 hours).
Preservation of the penumbra (the
partially damaged brain area around the
necrotic core) until reperfusion
• Lowering the temperature of the brain
• Glutamate receptor antagonists
• Barbiturates, tranquillizers
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Progression of ischemic
brain injury after stroke
No treatment
Neuroprotection without
reperfusion
Neuroprotection with reperfusion
tPA
Improve
d
outcome
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Start of thrombolysis
2:15
(early)
6:00
(late)
• Effective and safe – in elderly as well!
• Stroke outcome 30% better
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Stroke-induced responses in
the brain parenchyma
Timeline overview
of stroke induced
response
Days 0
Hours 0
0
Min
Realistic
Therapeut
ic Window
1
60
2
4.
5
1
12
Loss of Electrochemical
Oxidative stress
gradients/Depolarization
Excitotoxicity
Immediate Early Genes
Transcription factor activation
Protein misfolding/Heat Shock
ER stress/MisfoldedProteins
protein
response
Irreversible Mitochondrial
damage
Cytokines/chemokines
Inflammation
Reactive astrocyte
Gliosis
Angiogenesis/Regeneration
Salvageable
Loss of
Therapeutic
Benefit
4
7
Phases of stroke-induced
alterations in the brain
parenchyma
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INSULT
Therapeutic
window:
Hypothermia
or others
Primary energy failure (Minutes)
Na+ overload
Excitotoxici
ty
Cerebral
Reperfusio
n
metabolism transiently
IMMEDIATE
necrotic
cell death
recovers
Ca ++
overload
ROS, NO
Secondary phase (Hours to days)
Between 6-72 h after insult
Mitochondrial
dysfunction
Caspases activation
Hypoxic
ischemic
injury
DELAYED
apoptotic
cell death
brain
Interventions NEED TO BE WITHIN 6 h of
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Causes of hemorrhagic stroke
1 Parenchymal bleeding
• Hypertension , especially combined by druginduced iatrogenic coagulopathies, amyloid
angiopathy
• Hypertension alone and in combination with
drug-induced (coumarins) coagulopathy
frequently occur in the elderly resulting in
stroke. Their combination causes gradual slow
bleeding that frequently leads to death.
2 Subarachnoidal bleeding
• rupture of cerebral aneurysm, arterio-venous
malformation, head trauma, coagulopathies,
amyloid angiopathy
• Head trauma is especially prevalent in the
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Consequences of strokes
Combination of mechanisms
An ischemic stroke may be combined with local bleeding
due to widespread collateral circulation and
thrombolytic or anti-coagulant therapy.
From damaged tissues in a hemorrhagic stroke
vasoconstrictor substance may be released, leading to
ischemia nearby.
Brain edema with increased intracranial pressure
High intracranial pressure (Monroe-Kelly doctrine) may
induce headache, nausea, vomiting, disturbed vision,
Cushing reflex (high blood pressure and bradycardia),
irregular breathing, confusion, convulsions, even
death due to herniation
Focal symptoms
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Other complications of
strokes in the elderly
Loss of former motor performance,
immobilization
• muscle atrophy
• limb contracture
• pneumonia
• deep venous thrombosis
• pressure ulcers
• loss of former activities, isolation,
depression
Aggressive diagnostic tests and
hospitalization
• leading to loss of self-confidence and