Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

NEUROLOGICAL DISORDERS IN THE ELERLYPART I

Miklós Székely and Gyula BakóMolecular and Clinical Basics of Gerontology – Lecture 16

Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011

TÁMOP-4.1.2-08/1/A-2009-0011

Neurological disorders in the elderlyAge-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

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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 agingLarge individual differences!

Neurological disorders in the elderly

TÁMOP-4.1.2-08/1/A-2009-0011The 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

TÁMOP-4.1.2-08/1/A-2009-0011The 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

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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

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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/m

in/1

00 g

)

80 100 18020

50

80

14020

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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.

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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.

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Disorders of CBF in the elderly: global cerebral ischemiaCauses of global ischemia in the elderly1 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.

TÁMOP-4.1.2-08/1/A-2009-0011Disorders of cerebral blood flow in the elderly: focal cerebral infarctionStroke = 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%

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Prevalence of stroke by age and sex (1999-2002)

Age (years)

% o

f pop

ulat

ion

0.41.1 1.2

3.1

6.6

12.0

0.3 0.82.1

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+

MenWomen

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Types of focal ischemic damage1 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.

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Causes of ischemic stroke1 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 embolisationSource: 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

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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 5 In this case the strongest risk factors are

hypertension and sleep apnea syndrome

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Other causes of cerebral ischemiaHypertensive encephalopathy Multiple focal microinfarctions in the brainMechanism: 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 developVasculitis, collagenoses, coagulation disordersAcute severe exsiccosis Disorders of microcirculation lead to focal neurological symptoms and confusion.

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Mechanisms of ischemic injury of the brainImpaired metabolism, deficient ATP production1 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.

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Mechanisms of ischemic brain damage

Acute neurochemical changes after Ischemic StrokeVessel occlusion Thrombolysis /

Mechanical embolectomyBlood flow reduction

Glucose and O2 deprivation

Cytoskeletal disruption

Failure of glutamate homeostasis

release re-uptake

EXCITOTOXICITY

Mitochondrial damage

Decreased Ca2+ buffering Ca2+

Oxidative stressROS

NO / PeroxynitriteLipid peroxidation

Irreversible cell damageActivation of cell death

mechanisms

ATP Depletion/Energy Failure

Anaerobic glycolysis

Lactic acidosis H+

Electrochemical gradient loss:

Influx of Ca2+, Na+, Cl- H2OEfflux of K+

Depolarization

Reverse Na+/Ca2+ exchangeOpening of Ca channels

(VSCC)Ca2+ release from internal

storesEndoplasmic reticulum

stressCytotoxicedema

TÁMOP-4.1.2-08/1/A-2009-0011Therapeutic and/or preventive measures in ischemic brain injuryTherapeutic measuresFollowing 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

TÁMOP-4.1.2-08/1/A-2009-0011Progression of ischemic brain injury after strokeNo treatment

Neuroprotection without reperfusion

Neuroprotection with reperfusion

Improved outcome

tPA

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2:15 (early) 6:00 (late)

Start of thrombolysis

• Effective and safe – in elderly as well!• Stroke outcome 30% better

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Realistic Therapeutic

Window

Stroke-induced responses in the brain parenchymaTimeline overview of

stroke induced response

Loss of Electrochemical gradients/Depolarization

DaysHoursMin

Salvageable TissueLoss of Therapeutic

Benefit

000

160

2 124.51 4 7

Oxidative stress

ExcitotoxicityImmediate Early Genes

Transcription factor activationProtein misfolding/Heat Shock Proteins

ER stress/Misfolded protein responseIrreversible Mitochondrial damage

Cytokines/chemokinesInflammation

Reactive astrocyteGliosis

Angiogenesis/Regeneration

TÁMOP-4.1.2-08/1/A-2009-0011Phases of stroke-induced alterations in the brain parenchyma

INSULT

IMMEDIATEnecrotic

cell death

DELAYEDapoptoticcell death

Therapeuticwindow:

Hypothermiaor 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

ReperfusionNa+ overloadExcitotoxicity

Mitochondrial dysfunctionCaspases activation

Ca ++ overloadROS, NO

Hypoxic ischemic brain injury

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Causes of hemorrhagic stroke1 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.

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Consequences of strokesCombination of mechanismsAn 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 symptomsDepending 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.

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Other complications of strokes in the elderlyLoss of former motor performance,

immobilization• muscle atrophy• limb contracture• pneumonia• deep venous thrombosis• pressure ulcers• loss of former activities, isolation, depressionAggressive diagnostic tests and hospitalization• leading to loss of self-confidence and

motivationRehabilitation must start early.Support of family members and friends is

essential.