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
NEUROLOGICAL
DISORDERS IN THE ELERLY
PART I
Miklós Székely and Gyula Bakó
Molecular and Clinical Basics of Gerontology – Lecture 16
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
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 age-related 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 diminishes
• The number of receptor binding sites decreases
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
Large individual differences!
Neurological disorders in the elderly
The most common aging-associated neurological disorders (outline)
• 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
• Peripheral neuropathies
The most common aging-associated neurological disorders (outline)
• 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
- dizziness (vertigo) in the elderly
• Peripheral neuropathies
General characteristics of the cerebral blood flow (CBF) I
• 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 60-140/160 mmHg mean arterial pressure (a function of systolic and diastolic blood pressure taking into consideration the systolic and diastolic times), CBF remains stable
• Cerebral vessels show different regulation: metabolic products (CO2, H+, adenosine, potassium) cause vasodilation, CO2 , H+ elicit vasoconstriction
• No direct vasoconstrictor effect of the sympathetic tone
Autoregulation of CBF
CBF is maintained at an optimal level between 60 mmHg and 140 mmHg mean arterial pressure (MAP) due to vascular adaptation.
MAP (mmHg)
CBF (ml/min/100 g)
80 100 180
20 50 80
140 20
General characteristics of the cerebral blood flow (CBF) II
• 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 develops. The brainstem may tolerate 20-30 min of ischemia.
• No benefit of ischemic preconditioning (activation of adaptive mechanisms upon short-term ischemia) in the brain.
Alterations of cerebral blood flow (CBF) in the elderly
• 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.)
• The structure of the vessels is also altered.
• The reactivity of the arterioles is impaired with aging.
• CBF autoregulation is largely maintained in the course of
healthy aging , but not in presence of vascular abnormalities.
Disorders of CBF in the elderly: global cerebral ischemia
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 ischemia in global circulatory disorders.
Inappropriate antihypertensive treatment may also enhance the risk in old populations.
Disorders of cerebral blood flow in the elderly: focal cerebral infarction
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%
• Hemorrhagic stroke (parenchymal vs.
subarachnoidal bleeding) below 20%
Prevalence of stroke by age and sex (1999-2002)
Age (years)
% of population
0.4 1.1 1.2
3.1
6.6
12.0
0.3 0.8
2.1
3.0
6.3
11.5
0,0 2,0 4,0 6,0 8,0 10,0 12,0 14,0
20 - 34 35 - 44 45 - 54 55 - 64 65 - 74 75+
Men Women
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!
2 Permanent ischemia (ischemic stroke)
Rapid or slowly developing irreversible progressive
ischemia with permanent complications.
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 acute myocardial infarction), from an atrial one (in atrial fibrillation, an especially prevalent
cause in the elderly) or from a large atherosclerotic
plaque of an a. carotis interna
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
5 In this case the strongest risk factors are
hypertension and sleep apnea syndrome
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 Acute severe exsiccosis
Disorders of microcirculation lead to focal neurological symptoms and confusion.
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
Ischemia leads to activation of xanthine oxidases, free radical
formation, cell damage, reduction in vasodilatory NO production.
Mechanisms of ischemic brain damage
Acute neurochemical changes after Ischemic Stroke
Vessel occlusion Thrombolysis /
Mechanical embolectomy Blood flow reduction
Glucose and O2 deprivation
Cytoskeletal disruption
Failure of glutamate homeostasis
release re-uptake
EXCITOTOXICITY Mitochondrial damage
Decreased Ca2+
buffering
Ca2+
Oxidative stress ROS
NO / Peroxynitrite Lipid peroxidation Irreversible cell damage
Activation of cell death mechanisms ATP Depletion/Energy Failure Anaerobic glycolysis
Lactic acidosis H+
Electrochemical gradient loss:
Influx of Ca2+, Na+, Cl- H2O Efflux of K+
Depolarization
Reverse Na+/Ca2+ exchange Opening of Ca channels
(VSCC)
Ca2+ release from internal stores
Endoplasmic reticulum stress Cytotoxic edema
Therapeutic and/or preventive
measures in ischemic brain injury
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
Progression of ischemic brain injury after stroke
No treatment
Neuroprotection without reperfusion
Neuroprotection with reperfusion
Improved outcome
tPA
2:15 (early) 6:00 (late)
Start of thrombolysis
• Effective and safe – in elderly as well!
• Stroke outcome 30% better
Realistic Therapeutic
Window
Stroke-induced responses in the brain parenchyma
Timeline overview of stroke induced response
Loss of Electrochemical gradients/Depolarization
Days Hours Min
Salvageable Tissue
Loss of Therapeutic Benefit
0 0 0
1 60
2 4.5 12
1 4 7
Oxidative stress Excitotoxicity Immediate Early Genes Transcription factor activation Protein misfolding/Heat Shock Proteins ER stress/Misfolded protein response Irreversible Mitochondrial damage Cytokines/chemokines Inflammation Reactive astrocyte Gliosis Angiogenesis/Regeneration
Phases of stroke-induced
alterations in the brain parenchyma
INSULT
IMMEDIATE necrotic cell death
DELAYED apoptotic cell death
Therapeutic window:
Hypothermia or others
Interventions NEED TO BE WITHIN 6 h of insult
Primary energy failure (Minutes)
Secondary phase (Hours to days) Between 6-72 h after insult
Cerebral metabolism transiently recovers Reperfusion
Na+ overload Excitotoxicity
Mitochondrial dysfunction Caspases activation
Ca ++ overload ROS, NO
Hypoxic ischemic brain injury
Causes of hemorrhagic stroke
1 Parenchymal bleeding
• Hypertension , especially combined by drug-induced 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 elderly due to
frequent falls. Rigidity of bridge veins linking the dura and the brain increase risk for bleeding during head trauma.
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
Depending on the site of injury, disturbances of vision, of speech,
dysphagia, sensory (e.g. central pain syndrome) and motor dysfunctions may develop.
Cognitive dysfunctions affect the patient and family.
