PATHOPHYSIOLOGY OF NERVOUS SYSTEM DISEASES

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PATHOPHYSIOLOGY OF NERVOUS SYSTEM DISEASES
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OVERWIEV

• Seizures and Epilepsy
• Cerebrovascular Diseases (Ischemic stroke)
• Dementias (Alzheimers Disease)
• Movement Disorders (Parkinsons Disease)
• Motor Neuron Diseases (ALS)
• Demyelinating Diseases (Multiple Sclerosis)
• Neuromuscular Junction Diseases (Myasthenia
  Gravis)
• Meningitis (Acute Bacterial Meningitis)
• Stress

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SEIZURES AND EPILEPSY

• Seizure is and abnormal discharge of electrical
  activity within the brain.
• It is a rapidly evolving disturbance of brain
  function that may produce impaired consciousness,
  abnormalities of sensation or mental function or
  convulsive movements.
• Convulsions are episodes of widespread and
  intense motor activity

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• Epilepsy, a recurrent disorder of cerebral
  function marked by sudden, brief attacks of
  altered consciousness, motor activity or sensory
  phenomenon.
• Convulsive seizures are the most common form.
• Using the definition of epilepsy as two or more
  unprovoked seizures the incidence of epilepsy is
  0.3 to 0.5 in different populations throughout
  the world.
• Incidence increases with age, with 30 initially
  occurring before 4 years and 75 -80 before 20
  years.

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MECHANISM OF SEIZURE INITIATION AND PROPAGATION

• Partial seizure activity can begin in a very
  discrete region of cortex and then spread to
  neighboring regions i.e.
• There are two phases
• 1- the seizure initiation phase
• 2- the seizure propagation phase.
• The seizure initiation phase is characterized by
  two concurrent events in an aggregate of neurons
• 1- high-frequency burst of action potentials,
• 2- hypersynchronization.

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• The bursting activity is caused by a relatively
  long-lasting depolarization of the neuronal
  membrane due to influx of extracellular calcium.
• The influx of extracellular calcium leads to
• 1- the opening of voltage-dependent sodium
  channels,
• 2- influx of sodium,
• 3- Generation of repetetive action potentials.
• This is followed by a hyperpolarizing
  afterpotential mediated by GABA receptors or
  potassium channels, depending on the cell type.

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• Repetitive discharges leads to the following
• 1- an increase in extracellular potassium which
  blunts hyperpolarization and depolarization and
  depolarizes neighboring neurons,
• 2- accumulation of calcium in presynaptic
  terminals, leading to enhanced neurotransmitter
  release,
• 3- depolarization-induced activation of the
  N-methyl-D-aspartate (NMDA) subtype of the
  excitatory aminoacid receptor, which causes
  calcium influx and neuronal activation.

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• The recruitment of a sufficient number of neurons
  leads to
• a loss of the surrounding inhibition and
• propagation of seizure activity into contiguous
  areas via local cortical connections,
• and to more distant areas via long commissural
  pathways such as corpus callosum.

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Epileptogenic focus

• Group of brain neurons susceptible to activation
• Plasma membranes may be more permeable to ion
  movement
• Firing of these neurons may be greater in
  frequency and amplitude
• Electrical activity can spread to other
  hemisphere and then to the spinal cord

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Eliciting stimuli

• Hypoglycemia
• Fatigue
• Emotional or physical stress
• Fever
• Hyperventilation
• Environmental stimuli

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• Seizures
• Partial (focal/local)
• Simple, complex, secondary, generalized
• Generalized (bilateral/symmetric)
• Unclassified

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• Signs and symptoms vary
• petit mal almost imperceptible alterations
  in consciousness
• grand mal generalized tonic-clonic seizures
  dramatic loss of consciousness, falling,
  generalized tonic-clonic convulsions of all
  extremities, incontinence, and amnesia for the
  event.

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• Some attacks are proceeded by a prodrome a set
  of symptoms that warn of a seizure
• As the seizure begins, the patient may experience
  an aura mental, sensory or motor phenomena
• Others have no warning

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Phases of a grand mal seizure

• Tonic phase ( 10 -20 seconds) muscle
  contraction
• Epileptic cry respiration stops
• Clonic phase (1/2 -2 minutes) muscle spasms
  respiration is ineffective autonomic nervous
  system active (Cyanosis, excessive salivation,
  tongue or cheek biting may occur)
• Terminal phase (about 5 minutes) limp and quiet,
  EEG flat lines

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• 5-8 are at risk of status epilepticus a
  series of GTCS without regaining consciousness
  medical emergency
• Seizure activity lasts more than 30 minutes
• Acidosis
• Elevated pCO2
• Hypoglycemia
• Fall in blood pressure
• Can lead to severe brain damage or death

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CEREBROVASCULAR DISEASES

• Most frequent of all neurological problems
• Due to blood vessel pathology
• Lesions on walls of vessels (atherosclerosis)
• Occlusions of vessel lumen by thrombus or embolus
• Vessel rupture
• Alterations of blood quality
• CV disease leads to two types of brain
  abnormalities
• Ischemia (with or without infarct)
• Hemorrhage

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Cerebrovascular Accident(Stroke)

• Clinical expression of cerebrovascular disease a
  sudden, nonconvulsive focal neurological deficit
• Incidence
• third leading cause of death in U.S. half a
  million people a year one third will die from
  it
• Highest risk gt 65 years of age
• But about 1/3 (28) are lt 65 years old
• Tends to run in families
• More often seen in females

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Risk Factors

• Arterial hypertension
• Heart disease
• Myocardial infarction or endocarditis
• Atrial fibrillation
• Elevated plasma cholesterol
• Atherosclerosis
• Diabetes mellitus
• Oral contraceptives
• Smoking
• Polycythemia and thrombocythemia

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Sites for Atherosclerosis
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Stroke

• Classification based on underlying
  pathophysiologic findings
• 1- Oclussive stroke
• (Ischemia thrombotic and embolic)
• 2- Hemorrhagic stroke

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Major Types of Stroke
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Occlusive strokes

• Occurs with blockage of blood vessel by a
  thrombus or embolus
• Atherosclerosis is a major cause of stroke
• Can lead to thrombus formation and contribute to
  emboli
• May be temporary or permanent
• Thrombotic stroke
• 3 clinical types
• TIAs
• Stroke-in-evolution
• Completed stroke

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Transient Ischemic Attacks

• Last for only a few minutes, always less than 24
  hours
• All neurological deficits resolve
• Symptom of developing thrombosis

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Causes of TIA

• Thrombus formation
• Atherosclerosis
• Arteritis
• Hypertension
• Vasospasm
• Other
• Hypotension
• Anemia
• Polycythemia

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Stroke-in-evolution

• Can have abrupt onset, but develop in a
  step-by-step fashion over minutes to hours,
  occasionally, from days to weeks
• Characteristic of thrombotic stroke or slow
  hemorrhage

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Thrombotic CVA

• Involves permanent damage to brain due to
  ischemia, hypoxia and necrosis of neurons
• Most common form of CVA
• Causes
• Atherosclerosis associated with hypertension
• Diabetes mellitus, and vascular disease
• Trauma

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• May take years to develop, often asymptomatic
  until major narrowing of arterial lumen
• Anything that lowers systemic B.P. will
  exacerbate symptoms (60 during sleep)
• Area affected depends on artery and presence of
  anastomoses
• Area affected initially is greater than damage
  due to edema
• Infarcted tissue undergoes liquifaction necrosis

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Embolic stroke

• Second most common CVA
• Fragments that break from a thrombus outside the
  brain, or occasionally air, fat, clumps of
  bacteria, or tumors
• Impact is the same for thrombotic stroke
• Rapid onset of symptoms
• Often have a second stroke
• Common causes
• Atrial fibrillation
• Myocardial infarction
• Endocarditis
• Rheumatic heart disease and other defects

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Hemorrhagic Stroke

• Third most common, but most lethal
• Bleeding into cerebrum or subarachnoid space
• Common causes
• Ruptured aneurysms
• Vascular malformations
• Hypertension
• Bleeding into tumors
• Bleeding disorders
• Head trauma

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• Often a history of physical or emotional exertion
  immediately prior to event
• Causes infarction by interrupting blood flow to
  region downstream from hemorrhage
• Further damage by hematoma or ICP
• Onset less rapid than embolic CVA, evolving over
  an hour or two

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• Usually chronic hypertension, and B.P. may
  continue to rise
• About half report severe headache
• In about 70 hematoma expands, destroying vital
  brain centers, shifts of brain tissue, and death

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Pathophysiology of stroke

• Brain requires continuous supply of O2 and
  glucose for neurons to function
• If blood flow is interrupted
• Neurologic metabolism is altered in 30 seconds
• Metabolism stops in 2 minutes
• Cell death occurs in 5 minutes

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• Around the core area of ischemia is a border zone
  of reduced blood flow where ischemia is
  potentially reversible
• If adequate blood flow can be restored early (lt3
  hours) and the ischemic cascade can be
  interrupted
• less brain damage and less neurologic function
  lost

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Necrosis
Pneumbra

• Two kinds of ischemic insult
• 1. Cell damage ? cell death (acute cell necrosis,
  
• delayed cell
  degeneration)
• 2. Vascular (endothelial) damage ?
• (1) vasogenic edema ? pressure effect
• (2) reperfusion bleeding

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Symptoms depend on location

• Ophthalmic branch of internal carotid artery
  amaurosis fugax fleeting blindness
• Anterior or middle cerebral arteries
  contralateral monoparesis, hemiparesis,
  localized, tingling numbness in one arm, loss of
  right or left visual field or aphasia

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Clinical Manifestations of Stroke

• Affects many body functions
• Motor activity
• Elimination
• Intellectual function
• Spatial-perceptual alterations
• Personality
• Affect
• Sensation
• Communication

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Clinical ManifestationsMotor Function

• Most obvious effect of stroke
• Can include impairment of
• Mobility
• Respiratory function
• Swallowing and speech
• Self-care abilities
• Characteristic motor deficits (contra-lateral)
• Loss of skilled voluntary movement
• Impairment of integration of movements
• Alterations in muscle tone (flaccid ? spastic)
• Alterations in reflexes (hypo ? hyper)

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Clinical ManifestationsCommunication

• Patient may experience aphasia when stroke
  damages the dominant hemisphere of the brain
• Aphasia total loss of comprehension and use of
  language
• Dysphasia difficulty with comprehension and use
  of language
• Classified as nonfluent or fluent
• Dysarthria
• Disturbance in the muscular control of speech
• Impairments in pronunciation, articulation, and
  phonation NOT meaning or comprehension

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Clinical ManifestationsAffect

• May have difficulty controlling their emotions
• Emotional responses may be exaggerated or
  unpredictable
• Depression , impaired body image and loss of
  function can make this worse
• May be frustrated by mobility and communication
  problems

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Clinical ManifestationsIntellectual Function

• Memory and judgment may be impaired,
• Left-brain stroke more likely to result in
  memory problems related to language
• Spatial-Perceptual Alterations
• Spatial-perceptual problems may be divided into
  four categories
• Incorrect perception of self and illness (may
  deny illness or body parts)
• Erroneous perception of self in space (e.g.,
  neglect all input from affected side distance
  judgement
• Inability to recognize an object by sight, touch,
  or hearing
• Inability to carry out learned sequential
  movements on command

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Manifestations of Right-Brain and Left-Brain
Stroke
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Neurodegenerative Disorders
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Definition

• Neurodegenerative disease is a condition which
  affects brain function. Neurodegenerative
  diseases result from deterioration of neurons.
• They are divided into two groups
• conditions affecting memory and conditions
  related to dementia
• conditions causing problems with movements.
• Examples
• Alzheimers
• Parkinsons
• Huntingtons
• Creutzfeldt-Jakob disease
• Multiple Sclerosis
• Amyotrophic Lateral Sclerosis (ALS or Lou
  Gehrig's Disease)

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DEMENTIAS

• Learning
• a change of behaviour based on previous
  experience, an entry to memory
• Memory
• storage of information for further utilization

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• Process of memory
• creation of the memory trace
• consolidation of the memory trace
• retention
• evocation - evocation based on stimuli (reminder)
• - recall
• - recognition

trace consolidation
retention
evocation
trace creation
forgetting
warming of the trace extends retention,
decreases probability of forgetting
new exposition to the stimulus or evocation
retention
trace reconsolidation
Processes of trace consolidation and
reconsolidation are sensitive to disruptive
effects. In the phase of retention the memory
trace is more stable.
brain commotion, electroshock, hypoglycaemia,
hypothermia, intoxication (alcohol)
amnesia
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• Classification of memory according to persistance
• 1) short-term
• -seconds - minutes
• -restricted capacity, older information are
  overlapped with new one
• -information is then shifted into medium-term
  memory or forgotten
• 2) medium-term
• -minutes - hours
• -important information shifted into long-term
  memory, other forgotten
• 3) long-term
• -hours, days, years, permanently
• Working memory information is stored until it
  is used, then it is forgotten, belongs to
  medium-term memory

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• Declarative memory
• - information can be expressed verbally or as
  visual image
• - evocation is wilful
• 1) semantic abstract information
• 2) episodic - events
• 3) recognition recognition of objects
• Non-declarative memory
• - information can not be expressed verbally
• - evocation is unaware
• 1) motor patterns
• 2) conditioned reflexes
• 3) perceptive a cognitive patterns

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Structures involved in processes of learning and
memory

• 1- Hippocampus
• - Necessary for declarative memory
• - Emotional component and motivation in the
  learning process
• 2- Associative cortical areas
• 3- Septum
• 4- Corpus amygdaloideum ( emotional memory)
• 5- Entorhinal cortex
• 6- Cerebellum
• - motor learning, role in other types of
  learning
• 7- Striatum (motor learning)
• Injury and changes of these regions -structural,
  metabolic, changes of neuromediator systems
  (namely acetylcholine, glutamate, dopamine,
  noradrenalin)
• ? Learning and memory defects
• Learning and memory can be also influenced by
  changes of attention, motivation and emotions,
  sensory systems.
• Learned behaviour depends also function of motor
  system.

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MEMORY DISORDERS

• Amnesia complete loss of memory
• -retrograde loss of information acquired
  before the genesis of the amnesia
• - anterograde defect of storing new
  information
• Hypomnesia decrease of memory capacity
• Hypermnesia excessive and inadequate
  remembering of some facts
• Paramnesia distortion of stored information,
  the patient is confident at it is correct
• Memory delusion conviction about reality of an
  event, which did not happen, a kind of
  paramnesia
• Ekmnesia inaccurate time localisation of an
  event (which is memorized correctly)

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DISORDERS OF MIND AND INTELLIGENCE

• Dementia acquired disorder of cognitive
  functions, including memory
• Causes of dementia
• Alzheimers disease, vascular dementia,
  alcoholic dementia
• Picks disease, Parkinsons disease, Huntingtons
  chorea, infections, brain tumours, hydrocephalus,
  brain trauma, endocrinopathy
• temporary (reversible) disorders of cognitive
  functions (e.g. circulatory decompensation,
  dehydratation, hypothyroidism)
• Mental retardation developmental disorder of
  cognitive functions
• -slight independence, possibility of simple
  job
• -middle partial independence
• -severe limited self-service, speech limited
  to single words
• - deep inability of self-service, inability to
  speak

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Dementia is a loss of ordered neural function

• Discrimination and attending to stimuli
• Storing new memories and retrieving old
• Planning and delay of gratification
• Abstraction and problem solving
• Judgement and reasoning
• Orientation in time and space
• Language processing
• Appropriate use of objects
• Planning and execution of voluntary movements

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Course slow progression (5years or more)

• At first affects only short term memory, but
  gradually extends to long term
• Many experience restlessness
• Many patients retain insight, which leads to
  anxiety and depression
• Personality may be lost
• Ultimately, mute and paralyzed
• Death comes from infection

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ALZHEIMERS DISEASE

• Onset may be as young as 50, and incidence
  increases with age
• 6 of people over 65 years have AD
• Almost half over 85 have AD
• Diagnosis is by ruling out all other causes
  specific diagnosis only by biopsy or autopsy
• Pathology restricted to cerebral cortex,
  hippocampus, amygdala, and another basal nucleus
  called nucleus of Meynert.
• Nucleus of Meynert produces Acetylcholine.
• Its loss results in impaired neural function.

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ALZHEIMERS DISEASE

• The exact cause of AD is unknown.
• Several possible theroies being investigated
  include
• Loss of neurotransmitter stimulation by
  acetlytransferase,
• Mutation for encoding amyloid precursor protein
  (APP),
• Alteration in Apolipoprotein E, which binds
  ß-amyloid,
• Pathologic activation of N-methly-D-aspartate
  receptors resulting in an influx of excess
  calcium.

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ALZHEIMERS DISEASE

• Early-onset familial AD includes at least three
  gene defects
• APP (Chromosome 21)
• PSEN-1 (Presenilin-1) (Chromosome 14)
• PSEN-2 (Presenilin-2) (Chromosome 1).
• Late-onset FAD is linked to a defect in the
  Apolipoprotein E-4.
• ApoE helps carry cholesterol and fat in
  bloodstream
• 3 common forms
• e2, e3, e4
• Apo e4 most linked to leading to Alzheimers (1/3
  of cases?)
• Apo e2 may have protective effect

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Genetic and Environmental Factors in Alzheimers
Disease
Environment
Genes
Susceptibility Head trauma Vascular
factors HSV-1 Total cholesterol Hypertension
Susceptibility APOE-E ?4
Alzheimers Disease
Probabilistic ?-amyloid precursor Presenilin 1
Presenilin 2
Protective N.S.A.I.D.s Estrogen Education
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Pathophysiology of AD

• Each of these mechanisms linked to aggregation
  and precipitation of insoluble amyloid in brain
  tissue and blood vessels.
• Insoluble amyloid (abnormal amyloidal beta
  proteins) is called senile plaques, amyloid
  plaques, and neuritic plaques.
• Microscopically the Tau protein that normally
  stabilizes the microtubular transport system in
  the neurons detaches from the microtubule and
  forms insoluble helical filaments called a
  neurofibrillary tangle.

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Pathophysiology of AD

• Tangles are flame shaped.
• Cortical nerve cell processes become twisted and
  dilated because of accumulation of the same
  filaments that form tangles.
• Amyloid also is deposited in cerebral arteries,
  causing an amyloid angiopathy.
• Groups of nerve cells, especially terminal axons,
  degenerate and coalesce around an amyloid core.
• Microscopic examination of these areas of
  degeneration reveals plaquelike material known as
  senile plaques.

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Normal
Alzheimers Brain
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Pathophysiology of AD

• These plaques disrupt nerve-impulse transmission.
• ß-amyloid binds to the seven nicotinic Ach
  receptors on cholinergic neurons. (Degeneration
  of cholinergic neurons)
• This binding induces phospate groups to attach to
  Tau protein.
• Senile plaques and neurofibrillary tangles are
  more concentrated in the cerebral cortex and
  hippocampus.

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Alzheimers Brain
Control Brain
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Alzheimers Disease

• Clinical manifestations
• Insidious onset
• Forgetfulness increasing over time
• Memory loss
• Deteriorating ability for problem solving
• Judgment deteriorates
• Behavioral changes
• Labile

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PARKINSONS DISEASE
James Parkinson
1817
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Epidemiology

• Movement disorder(s)
• 1.5 million USA (120,000 UK)
• 3rd commonest cause of disability
• 1 over 60, 5 over 85
• Its peak age of onset is in the 60s.
• Familial clusters of autosomal dominant and
  recessive forms of PD comprise 5 of cases.
• Although most patients with PD appear to have no
  strong genetic determinant, epidemiologic
  evidence points to complex interaction between
  genetic vulnerability and environmental factors.

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Why?
?
?
Family history

• Rural living

Pesticide exposure
Gender (?)
Diet (bad food)
Age
Non-smoking
Head injury
Race (Caucasian)
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Where?

• Dopaminergic system
• Substantia nigra
• Striatum
• Other
• Basal ganglia (globus pallidus, subthalamic
  nucleus)
• Hippocampus, cortex, hypothalamus, thalamus
• Olfactory bulb
• Non-dopaminergic systems (locus coeruleus, raphe
  nuclei)

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Basics
Normal brain
Dopamine
Substantia Nigra
Striatum
Motor cortex via globus pallidus and thalamus
Movement
Parkinsons Disease
Dopamine
Substantia Nigra
Movement
Striatum
Movement
Motor cortex
M to c r x
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Pathophysiology

• Loss of DA neurones from SNPC
• Pigmented
• gt 80
• Degeneration of NS pathway
• Loss of caudate-putamen DA content

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In PD dopaminergic and other cells die due to a
combination of factors including

• 1- Genetic vulnerability,
• 2- Oxidative stress,
• 3- Proteosomal dysfunction,
• 4- Environmental factors MPTP (1-methyl-4-phenyl-
  1,2,3,6-tetrahydropyridine) and rotenone)

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Locus Gene Inheritance

• PARK1 a-Synuclein AD
• PARK2 Parkin AR
• PARK4 a-Synuclein AD
• PARK5 UCHL1 AD
• PARK7 DJ-1 AR
• PARK3,4,6,8,9 Unknown AD and AR
• PARK10 Unknown Late onset

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Parkin mutation

• Rare, juvenile-onset form of PD
• Lewy body pathology
• Parkin is involved in ubiquitin-proteasome system
• Breaks down proteins in the cell
• Parkin mutations may lead to accumulation of
  toxic proteins
• Parkin interacts with (degrades) synphilin-1 and
  a-synuclein
• Parkin may therefore be important in both fPD and
  nfPD
• Normal parkin may protects neurons from
• a-synuclein toxicity
• Proteasomal dysfunction
• Excitotoxicity
• Parkin may help to regulate the release of DA
  from SN
• Again provides link between genetics and sporadic
  PD

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Protein Degradation (Ubiquitin-Proteasome System)

• The cell's protein disposal system
• Perturbations may cause build up of toxic
  compounds
• Ubiquitin acts as a tag and marks proteins for
  degradation by proteasomes
• Proteasome inhibition accumulates
• a-synuclein
• e.g. p53, NFKB, and Bax all involved in
  apoptosis

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Where do free radicals come from?

• Mitochondrial electron transport chain
• Inflammatory response (released by e.g.
  microglia)
• Dopamine metabolism
• Nitric oxide (neuromodulator)
• Arachidonic acid metabolism pathway (pain, fever,
  inflammation)
• Xanthine oxidase pathway (purine catabolism)

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Pathophysiology

• PD is characterized by a neuronal accumulation of
  the presynaptic protein a-synuclein.
• Gross pathologic examination of the brain in PD
  reveals mild frontal atrophy with loss of the
  normal dark melanin pigment of the midbrain.

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Pathophysiology

• There is degeneration of the dopaminergic cells
  with the presence of Lewy bodies (LBs) in the
  remaining neurons and processes of the SN pars
  compacta (SNpc), other brainstem nuclei, and
  regions such as the medial temporal, limbic and
  frontal cortices.
• LBs have a high concentration of
• a-synuclein and are the pathologic
• hallmark of the disorder.

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Primary symptoms

• Rigidity - increased tone or stiffness in the
  muscles
• Tremor - 25 of patients experience very slight
  tremor or none at all
• Bradykinesia - slowness of movement
• Akinesia - impaired movement initiation and
  poverty of movement

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• Secondary symptoms
• Poor balance
• Depression
• Sleep disturbances
• Dizziness
• Stooped posture
• Constipation
• Dementia
• Problems with speech, breathing, swallowing, and
  sexual function

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Hoehn and Yahr Staging of PD

• Stage one
• Signs/symptoms unilateral
• Symptoms mild
• Symptoms inconvenient but not disabling
• Usually presents with tremor of one limb
• Changes in posture, locomotion and facial
  expression

• Stage two
• Symptoms are bilateral
• Minimal disability
• Posture and gait affected

• Stage five
• Invalidism complete
• Cannot stand or walk
• Requires constant nursing care

• Stage three
• Bradykinesia
• Impaired balance
• Moderately severe dysfunction

• Stage four
• Severe symptoms
• Walking limited
• Rigidity and bradykinesia
• Not self sufficient
• Tremor may decrease

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MOTOR NEURON DISEASES(Amyotrophic Lateral
Sclerosis)
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Amyotrophic Lateral Sclerosis

• Degenerative motor neuron disease that affects
  UMN LMN lying within the brain, spinal cord and
  peripheral nerves.
• They are responsible for controlling voluntary
  muscles in the arms, legs, and face. 

• Lou Gehrig

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ALS

• Definition rare, progressive neurological
  disorder characterized by loss of motor neurons
• Motor neurons in brain and spinal cord gradually
  degenerate
• Leads to death within 2-6yrs of diagnosis
• More common in men than women by ratio of 21

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• The myelin sheaths are destroyed and replaced
  with scar tissue
• Does not affect CN
• 3
• 4
• 6
• The patient is therefore able to
• Blink
• Move eye
• Cognition is left intact!

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• several cascades contribute to the degeneration
  of motor nerve cells
• .

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• Motor nerve degeneration is triggered by the
  death of the neuron cell body.
• Death of cell body leads to the degeneration of
  the axon.
• When axons die, the remaining must therefore
  innervate bigger muscle fibers, leading to the
  atrophy of muscle cells

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Pathophysiology of ALS

• ALS a/w mutant SOD1 (cytosolic Cu-Zn SOD).
• Thus, the levels of carbonyl proteins in the
  brain and the levels of free nitrotyrosine in the
  spinal cord elevate.
• ALS a/w neurofilament dysfunctions.
• (mutant heavy chain
• neurofilament subunit,
• increased peripherin
• expression)

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Pathophysiology of ALS

• Glutamate is the most abundant excitatory
  neurotransmitter in the CNS.
• Glutamate is removed from synapses by transport
  proteins on surrounding astrocytes and nerve
  terminals.
• In astrocytes, it is metabolized to glutamine.
• ALS a/w a loss of the astrocytic glutamate
  transporter protein excitatory amino acid
  transporter 2(EAAT2) and GluR2 receptor subunit.

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• the transporter is mutated in ALS patients.
• Thus, selective loss of glutamate transporter may
  cause excitotoxicity in ALS by increasing
  extracellular levels of glutamate.
• Too much exposure to glutamate is toxic to a
  neuron and cause destruction.

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• Etiology
• Unknown
• Men gt Women
• Clinical manifestations
• Progressive muscle weakness
• Atrophy
• Spasity
• Dysphagia
• Dysarthria
• Jaw Clonus
• Tongue fasciculation

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Demyelinating Diseases (Multiple Sclerosis)
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Multiple Sclerosis

• Focal, chronic, progressive, usually exacerbating
  and remitting demyelination of CNS tracts.
• Lesions can occur in a wide variety of locations
  and give rise to complex symptoms
• Areas of demyelination are called plaques, and
  can occur anywhere oligodendrocytes provide
  myelin sheath

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Onset

• Onset is between 20 and 40 years, rarely before
  15 or after 50
• Females Males 21

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ETIOLOGY

• Cause is still unknown
• Identified factors
• Autoimmune causes
• Human Leukocyte Antigens
• Viral causes
• Roseola virus

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Multiple Sclerosis

• Pathophysiology
• Autoimmune disease
• Demyelination of the myelin covering that
  protects the neurons of the brain and spinal cord

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• Demyelination
• Destruction of the myelin sheath ?
• Impaired transmission of nerve impulses
• Both the axon myelin are attacked
• Demyelinated axons
• Do not conduct normal action potentials
• Hyperexcitable (generate action potentials with
  minimal stimuli)
• Lesions are scattered in space and time

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• Multiple scarred areas visible on macroscopic
  examination of
• the brain (plaques).
• Plaques vary in size from 1-2mm to several cm
• Lesions evolve over time
• Initially, contain T lymphocytes and macrophages
  which infiltrate areas of demyelination.
• As lesion evolves, macrophages scavenge myelin
  debris.
• Then scar tissue forms.

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Immunology

• Autoimmune disease modulated by T lymphocytes
• Etiology not completely understood
• Auto-antigen is most likely a myelin protein

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• Neural antigens are processed by antigen
  presenting cells in lymph nodes and presented to
  T cells
• Sensitized memory T cells migrate to the CNS,
  where they are reactivated by antigen presenting
  macrophages

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• Proinflammatory cytokines are secreted.
• Enhance expression of adhesion molecules by
  vascular endothelium, alter permeability of the
  blood-brain barrier, and induce a second wave of
  inflammatory cell recruitment
• Inflammatory response leads to localized
  demyelination

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• Myelin basic protein (MBP) is probably an
  important T cell antigen in MS.
• Activated MBP-reactive T cells are often found in
  bloods or CSF of MS patients.
• There are autoantibodies which directed against
  myelin oligodendrocyte glycoprotein (MOG).
• Cytokines IL-2, TNF-a and IFN-?

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Presenting Symptoms

• Visual disorders (optic neuritis blurring of
  central visual field, loss of brightness in one
  eye, eye pain)
• Movement coordination and balance problems
• Numbness and tingling (paresthesia and
  dyesthesia)
• Spacticitiy
• Tremors
• Weakness and fatigue
• Bladder and bowel disorders
• Diagnosis by exclusion

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Neuromuscular Junction Diseases
(Myasthenia Gravis)
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Myasthenia Gravis (MG)

• Autoimmune disorder
• Antibody destruction of Ach receptors
• Skeletal muscle weakness
• Eye muscles
• Facial, speech, mastication
• Exacerbations
• Frequently associated with hyperplasia of thymus
  or thymoma
• Association with other autoimmune diseases

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Epidemiology

• Frequency
• Worldwide prevalence 1/10,000 (D)
• Mortality/morbidity
• Recent decrease in mortality rate due to advances
  in treatment
• 3-4 (as high as 30-40)
• Risk factors
• Age gt 40
• Short history of disease
• Thymoma
• Sex
• F-M (64)
• Mean age of onset (M-42, F-28)
• Incidence peaks- M- 6-7th decade F- 3rd decade

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Neuromuscular Junction (NMJ)

• Components
• Presynaptic membrane
• Postsynaptic membrane
• Synaptic cleft
• Presynaptic membrane contains vesicles with
  Acetylcholine (ACh) which are released into
  synaptic cleft in a calcium dependent manner
• ACh attaches to ACh receptors (AChR) on
  postsynaptic membrane

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• Neuromuscular Junction (NMJ)
• The Acetylcholine receptor (AChR) is a sodium
  channel that opens when bound by ACh
• There is a partial depolarization of the
  postsynaptic membrane and this causes an
  excitatory postsynaptic potential (EPSP)
• If enough sodium channels open and a threshold
  potential is reached, a muscle action potential
  is generated in the postsynaptic membrane

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Pathophysiology

• In MG, antibodies are directed toward the
  acetylcholine receptor at the neuromuscular
  junction of skeletal muscles
• Results in
• Decreased number of nicotinic acetylcholine
  receptors at the motor end-plate
• Reduced postsynaptic membrane folds
• Widened synaptic cleft

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Immunology

• It is the prototype autoimmune disease mediated
  by blocking auto-antibodies
• A patient withthis disease produces autoAbs to
  the Ach receptors on the motor end-plates of
  muscles

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• Binding of these AutoAbs to the receptors blocks
  the normal binding of Ach and also induces
  complement-mediated degradation of the receptors,
  resulting in progressive weakening of the
  skeletal muscles

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Clinical presentation

• Muscle strength
• Facial muscle weakness
• Bulbar muscle weakness
• Limb muscle weakness
• Respiratory weakness
• Ocular muscle weakness

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Clinical presentation

• Facial muscle weakness is almost always present
• Ptosis and bilateral facial muscle weakness
• Occular muscle weakness
• Asymmetric
• Usually affects more than one extraocular muscle
  and is not limited to muscles innervated by one
  cranial nerve
• Weakness of lateral and medial recti may produce
  a pseudointernuclear opthalmoplegia
• Ptosis caused by eyelid weakness
• Diplopia is very common

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Meningitis(Acute Bacterial Meningitis)
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Definition

• Meningitis inflammation of the leptomeninges
  (the tissues surrounding the brain and spinal
  cord)
• Bacterial meningitis
• Aseptic meningits infectious or noninfectious
• Viral Rickettsiae
• Mycoplasma, Fungal
• Spirochetes syphilis, Lyme
• Protozoa malaria
• Malignancy
• Lupus erythematous
• Lead or mercury poisoning

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Meningitis

• The most common bacterial pathogens are
• Haemophili influenzai
• Affected kids lt 5 yrs
• H influenzae vaccine (Hib)
• Streptococcus pneumoniae
• Affects age 19-59
• Neisseria meningitides
• Easily transmitted to others
• Least lethal

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Pathophysiology

• Once in CSF, the absence of antibodies
  complement components allows bacterial infection
  to flourish
• Cascade of events
• Cell wall and membrane products of organism
  disrupt capillary endothelium of CNS (BBB)
• Margination and transmigration of PMNs across
  endothelia in CSF
• Release of cytokines and chemokines into the CNS
• Inflammation of subarachnoid space
• Mortality 3 to 13
• Rate varies with organism
• Higher with gram negative organism
• Neurologic Sequelae 10 of surviving patients

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Meningitis

• Clinical manifestations
• SS of I-ICP
• H/A
• ?LOC
• Vomiting
• Papilledema
• Hydrocephalus

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Meningitis

• Clinical manifestations
• Onset
• Abrupt
• General SS
• Nuchal rigidity
• Positive Kernig's
• Positive Brudzinskis
• Photophobia

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Physical Findings
Kernigs sign

• Brudzinskis sign

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Opisthotonus
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Stress and Disease
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Stress

• A person experiences stress when a demand exceeds
  a persons coping abilities, resulting in
  reactions such as disturbances of cognition,
  emotion, and behavior that can adversely affect
  well-being
• General Adaptation Syndrome (GAS)-response to
  stressors
• Three stages
• Alarm stage
• Arousal of body defenses
• Stage of resistance or adaptation
• Mobilization contributes to fight or flight
• Stage of exhaustion
• Progressive breakdown of compensatory mechanisms

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GAS Activation

• Alarm stage
• Stressor triggers the hypothalamic-pituitary-adren
  al (HPA) axis
• Activates sympathetic nervous system
• Resistance stage
• Begins with the actions of adrenal hormones
• Exhaustion stage
• Occurs only if stress continues and adaptation is
  not successful

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Psychoneuroimmunologic Mediators

• Interactions of consciousness, the brain and
  spinal cord, and the bodys defense mechanisms
• Corticotropin-releasing hormone (CRH) is released
  from the hypothalamus
• CRH is also released peripherally at inflammatory
  sites
• Immune modulation by psychosocial stressors leads
  directly to health outcomes

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Central Stress Response

• Catecholamines
• Released from chromaffin cells of the adrenal
  medulla
• Large amounts of epinephrine small amounts of
  norepinephrine
• a-adrenergic receptors
• a1 and a2
• ß-adrenergic receptors
• ß1 and ß2
• Mimic direct sympathetic stimulation

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Central Stress Response

• Cortisol (hydrocortisone)
• Activated by adrenocorticotropic hormone (ACTH)
• Stimulates gluconeogenesis
• Elevates the blood glucose level
• Protein anabolic effect in the liver catabolic
  effect in other tissues
• Lipolytic in some areas of the body, lipogenic in
  others
• Powerful anti-inflammatory/immunosuppressive
  agent

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Central Stress Response
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Central Stress Response
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Stress-Induced Hormone Alterations

• Female reproductive system
• Cortisol exerts inhibiting effects by suppressing
  the release of luteinizing hormone, estradiol,
  and progesterone
• Stress suppresses hypothalamic gonadotropin-releas
  ing hormone
• Estrogen stimulates the HPA axis

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Stress-Induced Hormone Alterations

• Endorphins and enkephalins
• Proteins found in the brain that have
  pain-relieving capabilities
• In a number of conditions, individuals not only
  experience insensitivity to pain but also
  increased feelings of excitement, positive
  well-being, and euphoria

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Stress-Induced Hormone Alterations

• Growth hormone (somatotropin)
• Produced by the anterior pituitary and by
  lymphocytes and mononuclear phagocytic cells
• Affects protein, lipid, and carbohydrate
  metabolism and counters the effects of insulin
• Enhances immune function

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Stress-Induced Hormone Alterations

• Prolactin
• Released from the anterior pituitary
• Necessary for lactation and breast development
• Prolactin levels in the plasma increase as a
  result of stressful stimuli
• Oxytocin
• Produced by the hypothalamus
• May promote reduced anxiety

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Stress-Induced Hormone Alterations

• Testosterone
• Secreted by Leydig cells
• Regulates male secondary sex characteristics
• Testosterone levels decrease due to stressful
  stimuli

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Stress Response

• Amygdala is the brains alarm system- it scans
  sensory In developing brains these stress
  neuro-hormones also inhibit neural development
• It can act independently of the neo-cortex
• Stores memories and initiate response repertoires
  without conscious involvement can initiate
  secretion of adrenaline/cortisol
• Massive secretion of neuro-hormones at time of
  trauma leads to long term potentiation of
  traumatic memories

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Anxiety Bell Curve

• Anxiety increases to a level where performance
  decreases
• Speech centres shut down, increased blood flow
  motor areas
• Over-arousal can quickly lead to aggression

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Stress, Personality, Coping, and Illness

• A stressor for one person may not be a stressor
  for another
• Psychologic distress
• General state of unpleasant arousal after life
  events that manifests as physiologic, emotional,
  cognitive, and behavior changes
• Coping
• Managing stressful demands and challenges that
  are appraised as taxing or exceeding the
  resources of the person

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Stress Personality CopingIllness
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Aging and Stress

• Stress-age syndrome
• Excitability changes in the limbic system and
  hypothalamus
• Increased catecholamines, ADH, ACTH, and cortisol
• Decreased testosterone, thyroxine, and other
  hormones
• Alterations of opioid peptides
• Immunodepression
• Alterations in lipoproteins
• Hypercoagulation of the blood
• Free radical damage of cells