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Neurological disorders in the elerly Part I

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.

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Neurological disorders in the elerly Part I

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  1. 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 Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

  2. 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 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 NeurologicaldisordersintheelerlyPart I

  3. 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

  4. 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 • Large individual differences!

  5. 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

  6. 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

  7. 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

  8. Autoregulation of CBF • CBF is maintained at an optimal level between 60 mmHg and 140 mmHg mean arterial pressure (MAP) due to vascular adaptation. 80 CBF (ml/min/100 g) 50 20 20 80 100 140 180 MAP(mmHg)

  9. 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 bloodflow (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.

  10. 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.

  11. 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 autoregulationincreases the risk for cerebral ischemia in global circulatory disorders. • Inappropriate antihypertensive treatment may also enhance the risk in old populations.

  12. 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%

  13. Prevalence of stroke by age and sex (1999-2002) 14,0 Men 12.0 Women 11.5 12,0 10,0 8,0 % of population 6.6 6.3 6,0 4,0 3.1 3.0 2.1 2,0 1.2 1.1 0.8 0.4 0.3 0,0 20 - 34 35 - 44 45 - 54 55 - 64 65 - 74 75+ Age (years)

  14. 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.

  15. Causes of ischemic stroke • 1 Atherosclerosis of large vessels providing perfusion to the brain, e.g. severe obstruction of the a. carotisinterna 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. cerebrimediabranch • 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. carotisinterna

  16. 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

  17. 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.

  18. 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 xanthineoxidases, free radical formation, cell damage, reduction in vasodilatory NO production.

  19. Mechanisms of ischemic brain damage Acute neurochemical changes after Ischemic Stroke Thrombolysis / Mechanical embolectomy Vessel occlusion Blood flow reduction Anaerobic glycolysis Glucose and O2deprivation Lactic acidosis H+ ATP Depletion/Energy Failure Cytoskeletal disruption Electrochemical gradient loss: Influx of Ca2+, Na+, Cl- H2O Efflux of K+ Mitochondrial damage Decreased Ca2+ buffering Failure of glutamate homeostasis releasere-uptake  Ca2+ Depolarization Reverse Na+/Ca2+ exchange Opening of Cachannels (VSCC) Ca2+ release from internal stores Endoplasmicreticulum stress Oxidative stress ROS NO / Peroxynitrite Lipid peroxidation EXCITOTOXICITY Irreversible cell damage Activation of cell death mechanisms Cytotoxic edema

  20. 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

  21. Progression of ischemic brain injury after stroke No treatment Neuroprotection without reperfusion Neuroprotection with reperfusion Improved outcome tPA

  22. Start of thrombolysis 2:15 (early) 6:00 (late) • Effective and safe – in elderly as well! • Stroke outcome 30% better

  23. Stroke-induced responses in the brain parenchyma Realistic Therapeutic Window Timeline overview of stroke induced response 0 0 0 1 60 2 4.5 12 1 4 7 Days Hours Min Loss of Electrochemical gradients/Depolarization 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 • Loss of Therapeutic Benefit Angiogenesis/Regeneration • Salvageable Tissue

  24. Phases of stroke-induced alterations in the brain parenchyma INSULT Therapeuticwindow: Hypothermiaor others Primary energy failure (Minutes) IMMEDIATE necrotic cell death Na+ overload Excitotoxicity Reperfusion Cerebral metabolism transiently recovers Ca ++ overload ROS, NO Secondary phase(Hours to days) Between 6-72 h after insult DELAYED apoptotic cell death Mitochondrial dysfunction Caspases activation Hypoxic ischemic brain injury Interventions NEED TO BE WITHIN 6 h of insult

  25. Causes of hemorrhagic stroke • Parenchymal bleeding • Hypertension , especially combined by drug-induced iatrogenic coagulopathies, amyloidangiopathy • 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. • Subarachnoidal bleeding • rupture of cerebralaneurysm, arterio-venousmalformation, head trauma, coagulopathies, amyloidangiopathy • 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 bleedingduring head trauma.

  26. 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.

  27. 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 motivation • Rehabilitation must start early. • Support of family members and friends is essential.

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