Brain Damage

1
Chapter 10

• Brain Damage Neuroplasticity

2
Causes of Brain Damage

• Brain tumors
• Cerebrovascular disorders stokes
• Cerebral hemorrhage
• Cerebral ischemia
• Closed-head injuries
• Infections of the brain
• Bacterial infections
• Viral infections
• Neurotoxins
• Genetic factors
• Down syndrome
• Programmed cell death

3
Brain Tumors

• Tumor (neoplasm) mass of cells that grows
  independently of the rest of the body
• Meningiomas
• Infiltrating tumors

4
Meningiomas

• 20
• Tumors that grow between the meninges
• All encapsulated tumors tumors that grow within
  their own membrane
• Influence function of the brain pressure
  exerted on surrounding tissue
• Almost always benign
• Once removed, little risk of further growth in
  the body

5
Infiltrating Tumors

• Grow diffusely through surrounding tissue
• Usually malignant tumors
• Difficult to remove or destroy completely,
  cancerous tissue that remains continues to grow
• 10 are metastatic tumors
• Do not originate in the brain
• Grow from infiltrating tumor fragments carried to
  the brain by the bloodstream

6
Cerebrovascular Disorders Strokes

• Stroke sudden onset, cerebrovascular disorders
  that cause brain damage
• 2 major types
• Cerebral hemorrhage
• Cerebral ischemia

7
Stroke

• 3rd leading cause of death
• Most common cause of adult disability
• Common consequences of stroke
• Amnesia, aphasia, paralysis, coma
• Infarct area of dead or dying tissue produced
  by the stroke
• Penumbra dysfunctional area surrounding the
  infarct
• Goal of treatment following stroke is to save the
  penumbra

8
Cerebral Hemorrhage

• Bleeding in the brain
• Cerebral blood vessel ruptures and blood seeps
  into the surrounding neural tissue
• Cause
• bursting aneurysm
• Aneurysm
• pathological balloon-like dilation that forms in
  the wall of an artery at a point where the
  elasticity of the artery wall is defective
• Congenital
• Vascular poisons or infection

9
Cerebral Ischemia

• Disruption of the blood supply to an area of the
  brain
• 3 main causes
• Thrombosis
• Plug (thrombus) is formed and blocks blood flow
  at the site of its formation
• Thrombus blood clot, fat, oil, air bubble,
  tumor cells
• Embolism
• Plug (embolus) is carried by the blood from a
  larger vessel, where it was formed, to a smaller
  on, where it becomes lodged
• Arteriosclerosis
• Walls of blood vessels thicken and channels
  narrow (fat deposits)

10
Cerebral Ischemia

• Brain damage
• Glutamate
• After a blood vessel becomes blocked,
  blood-deprived neurons become overactive and
  release excessive amounts of glutamate
• Glutamate then over-activates glutamate receptors
  on postsynaptic cells (NMDA receptors)
• Large numbers of Na and Ca ions enter
  postsynaptic neurons
• Excessive internal concentrations of Na and Ca
  ions affect the postsynaptic neurons in 2 ways
• Trigger the release of excessive amounts of
  glutamate
• Spreading the toxic cascade
• Trigger a sequence of internal reactions that
  ultimately kill postsynaptic neurons

11
Cerebral Ischemia

• Ischemia-induced brain damage has 3 properties
• Takes a while to develop
• Does not occur equally in all parts of the brain
• Mechanisms vary somewhat from structure to
  structure within the brain
• Astrocytes play a role

12
Closed-Head Injuries

• Contusions damage to the cerebral
  circulatory system
• Brain hits skull
• Produces internal hemorrhaging
• Results in hematoma localized collection of
  blood
• Concussion disturbances of consciousness with
  no contusions or other structural damage
• Punch drunk dementia and cerebral scarring seen
  following repeated concussions

13
Infections of the Brain

• 2 types
• Bacterial
• Viral
• Resulting inflammation - encephalitis

14
Infections of the Brain

• Bacterial
• Cerebral abscess pockets of pus
• Meningitis inflammation of the meninges
• Fatal in 25 of adults
• Syphilis passes through contact with genital
  scores
• General paresis syndrome of insanity and
  dementia that results from a syphilitic infection

15
Infections of the Brain

• Viral Infections
• 2 types
• Particular affinity for neural tissue
• Attack neural tissue with no greater affinity
• Rabies affinity for NS
• Doesnt attack brain for at least 1 month
• Fatal
• Mumps herpes can attack NS, but no affinity

16
Neurotoxins

• Toxins can enter general circulation
• GI tract
• Lungs
• Skin
• Toxic psychosis chronic insanity produced by a
  neurotoxin
• Lead or mercury
• Antipsychotic drugs
• Tardive dyskinesia involuntary smacking and
  sucking movements of the lips, throusting and
  rolling of the tongue, lateral jaw movements,
  puffing of the cheeks
• Endogenous neurotoxins
• Antibodies
• Glutamate (under some instances)

17
Genetic Factors

• 23 pairs of chromosomes
• Accidents of cell division
• Abnormal chromosome
• Abnormal number of chromosomes
• Most genetic neuropsychological diseases
  abnormal recessive genes
• Why?

18
Genetic Factors

• Most neuropsychological diseases of genetic
  origin are caused by abnormal recessive genes
• 2 possible situations in which neuropsychological
  disorders are associated with dominant genes
• Abnormal dominant gene only manifests itself in
  rare environmental circumstances
• Example?
• Abnormal gene is not expressed until the
  individual is past puberty
• Example?

19
Down Syndrome

• Genetic accident
• 0.15 of births
• Usually occurs during ovulation
• Extra chromosome 21 is created in the egg
• 3 chromosome 21s in the zygote

20
Down Syndrome

• Probability increases with advancing maternal age

21
Genetics of DS

• Trisomy 21
• Caused by a nondisjunction event.
• a gamete (a sperm or egg cell) is produced with
  an extra copy of chromosome 21
• Cause of approximately 95
• 88 from nondisjunction in the maternal gamete
• 8 from nondisjunction in the paternal gamete.
• Nondisjunction is the failure of chromosome pairs
  to separate properly during cell division
• The result of this error is a cell with an
  imbalance of chromosomes

22
Down Syndrome

• Mosaicism
• When some of the cells in the body are normal and
  other cells have trisomy 21
• This can occur in one of two ways
• Nondisjunction event during early cell division
  in a normal embryo leads to a fraction of the
  cells with trisomy 21
• Down syndrome embryo undergoes nondisjunction and
  some of the cells in the embryo revert to the
  normal chromosomal arrangement.
• Variability in the fraction of trisomy 21, both
  as a whole and among tissues.
• Cause of 12

23
Down Syndrome

• Robertsonian translocation
• The long arm of chromosome 21 is attached to
  another chromosome, often chromosome 14 or itself
  (called an isochromosome)
• A person with such a translocation is
  phenotypically normal.
• During reproduction, there is a significant
  chance of creating a gamete with an extra
  chromosome 21
• Cause of 23 of observed cases of Down syndrome.
• No maternal age effect, and is just as likely to
  have come from fathers as mothers.

24
Down Syndrome

• Duplication of a portion of chromosome 21
• Region of chromosome 21 will undergo a
  duplication (rare)
• Leads to extra copies of some, but not all, of
  the genes on chromosome 21
• If the duplicated region has genes that are
  responsible for Down syndrome physical and mental
  characteristics, such individuals will show those
  characteristics
• Very rare

25
Down Syndrome

• Consequences
• Disfigurement
• Flattened skull and nose
• Folds of skin over the inner corners of the eyes
• Short fingers
• Retarded intellectual development
• Often serious medical complications

26
Programmed Cell Death

• Apoptosis
• Critical role in early development (Chapter 9)
• Critical role in brain damage
• Neural damage activate apoptotic programs
• Necrosis also occurs

27
http//video.google.com/videoplay?docid-553345702
2793145141
28
Overview

• Amyotrophic Lateral Sclerosis (ALS)
• Parkinsons Disease
• Huntingtons Disease
• Multiple Sclerosis

29
Amyotrophic Lateral Sclerosis (ALS)

• AKA Lou Gehrigs
• 2 people per 100,000
• 40 and 60 years of age
• Men are affected slightly more often than women
• According to the ALS Association, military
  veterans are at an increased risk of contracting
  ALS.
• 60 greater chance of the disease in military
  veterans than the general population.
• For Gulf War veterans, the chance is seen as
  twice that of veterans not deployed to the
  Persian Gulf

30
ALS

• Gradually worsening paralysis
• caused by loss of motor neurons
• Always fatal
• most patients die within 2-5 years of diagnosis
• No effective treatment

31
Causes of ALS

• Non-hereditary ALS
• Sporadic ALS
• Virus
• Exposure to neurotoxins or heavy metals
• Immune system abnormalities
• Enzyme abnormalities.
• Inadequate trophic support from muscle

• Hereditary ALS
• Familial ALS
• 10 of cases
• About 20 of these have a defective gene for the
  enzyme superoxide dismutase (SOD).
• enzyme responsible for scavenging free radicals
• Mutant SOD is neurotoxic.

32
Parkinsons Disease

• Movement disorder of middle and old age
• Affects 0.5 of the population
• Malefemale, 2.51

33
PD - Symptoms

• Initial symptoms
• Mild, slight stiffness or tremor of the fingers
• Increase in severity with advancing years
• Advanced symptoms
• Tremor during inactivity (not during voluntary
  movement)
• Muscular rigidity
• Difficulty initiating movement
• Slowness of movement
• Masklike face
• Pain and depression
• Dementia not typically associated with disease

34
PD - Cause

• No single cause
• Faulty genes
• Brain infections
• Strokes
• Tumors
• Traumatic brain injury
• Neurotoxins
• In majority
• No obvious cause, no family history

35
Genetic Links to PD

• 10 different gene mutations
• Mutation in the ceruloplasmin gene, which is
  involved in iron transport (1995)
• mutations in the PINK gene (2004)
• Parkin is a protein which in humans is encoded by
  the PARK2 gene (1998).
• Each of these gene mutation seen in different
  families
• Rare form of early onset PD
• All mutations have been found to disrupt the
  function of mitochondria

36
PD Brain Pathology

• Widespread degeneration
• Severe in substantia nigra
• Axons project via nigrostriatal pathway to
  striatum of basal ganglion

37
(No Transcript)
38
Parkinsons Disease

• Death of dopamine neurons of the substantia nigra
  
• loss of dopamine innervation of striatum
• Cause of this degeneration is unknown
• Clumps of proteins in surviving DA neurons of SN
• Lewy bodies

39
Treatments

• L-dopa
• Chemical from which DA is synthesized
• L-dopa is transformed into dopamine in the
  dopaminergic neurons by decarboxylase
• Not a permanent solution
• Becomes less and less effective with continued
  use
• Side effects involuntary movements

40
Treatments

• Deep brain stimulation
• Low intensity electrical stimulation is
  continuously applied to an area of the brain
• Sterotaxically implanted electrode
• Suprathalamic nucleus
• Once current is on, symptoms are alleviated
  within minutes
• Effectiveness slowly declines
• If stimulation is turned off, therapeutic
  improvements stop

41
Mouse Models of Parkinsons Disease

• MPTP 1-methyl-4-phenyl-1,2,3-6-thrahydropyridine
  
• Nonhuman primates respond to MPTP the same as
  humans
• Cell loss in substantia nigra
• Level of DA is greatly reduced
• Gross motor symptoms
• Deprenyl (monamine agoinst) blocks the effects
  of MPTP in the animal model
• Administration in early Parkinsons slows the
  progression of the disease

42
Mouse Model of PD

• TFAM gene is deleted from the genome in dopamine
  nerve cells only.
• Without TFAM, mitochondria cannot function
  normally.
• Energy production decreases severely in DA cells.
• Mice develop disease slowly in adulthood, like
  humans with Parkinson's disease
• Facilitate research aimed at finding novel
  medical treatments and other therapies.

43
Huntingtons Disease

• Progressive motor disorder of middle and old age
• Rare 1/10,000
• Strong genetic basis
• Associated with severe dementia

44
Symptoms - HD

• 1st motor signs
• Increased fidgetiness
• As disease develops
• Rapid, complex, jerky movements of entire limbs
• Motor and intellectual deterioration become
  severe
• Incapable of feeding, controlling bowel
  movements, recognizing own children
• No cure
• Death occurs 15 years after 1st symptom

45
Symptoms - HD

• Reported prevalence's of behavioral and
  psychiatric symptoms in HD
• Depressed mood ?3369
• Anxiety ?3461
• Irritability ?3873
• Apathy 3476
• Obsessive and compulsive 1052
• Psychotic 311

46
Cause HD

• Single dominant gene all carriers of the gene
  develop the disorder as do half their offspring
• HD gene is easily passed from parent to child
  because the 1st symptom does not appear until the
  parent is past reproductive years

47
(No Transcript)
48
Huntingtin

• Dominant gene that is mutated
• Identified in 1993
• Codes for the huntingtin protein
• Normal huntingtin protects neurons from
  apoptotic cell death
• Expressed throughout the brain
• Brain damage is largely restricted to striatum
  and cerebral cortex

49
(No Transcript)
50
Treatment

• None!

51
Multiple Sclerosis

• Progressive disease that attacks the myelin of
  axons in the CNS
• Typically attacks young people

52
MS

• 1st - Microscopic areas of degeneration on myelin
  sheathes
• Eventually - damage to myelin is so severe that
  axons become dysfunctional
• Ultimately many areas of hard scar tissue
  develop in CNS

53
MS

• Diagnosing MS is difficult
• Nature and severity of disorder depends on the
  number, size and position of the sclerotic
  lesions
• Lengthy periods of remission
• Occurs in 0.15 of Caucasians
• Risk of acquiring MS is higher in relatives of a
  person with the disease than in the general
  population
• monozygotic twins, concordance occurs in about
  35 of cases
• Malefemale, 12

54
(No Transcript)
55
Causes - MS

• Environmental
• More likely in people who spent childhood in cool
  climate
• Genetic
• Rare among certain groups
• Asians Africans
• IL2RA and the IL7RA, subunits of the receptor for
  interleukin 2 and interleukin 7

56
MS

• Autoimmune disorder
• Myelin is the focus of the faulty immune reaction
• Healing response of remyelination which occurs in
  early stages of disease, eventually fails

57
Treatment MS

• No cure
• Several drugs to slow the progression of the
  disease
• Corticosteriods
• management of acute attacks
• Interferons - proteins produced by the cells of
  the immune system in response to challenges by
  foreign agents
• chronic

58
Alzheimers Disease (AD)

• Most common cause of dementia
• As young as 40, risk is greater with advancing
  years
• 10 of population over 65
• 35 over 85

59
AD

• Progressive
• Early stages
• Selective decline in memory
• Intermediate stages
• Confusion, irritability, anxiety, deterioration
  of speech
• Advanced stages
• Complete deterioration
• Simple responses such as swallowing and
  controlling bladder are difficult
• Fatal

60
AD

• 3 Neurodegenerative Changes
• Neurofibrillary tangles (NFTs)
• Thread-like tangles of protein in the neural
  cytoplasm
• The microtubule-associated protein, tau, is the
  principal component of NFTs
• Amyloid plaques
• Clumps of scar tissue composed of degenerating
  neurons and amyloid (protein)
• Amyloid present in normal brains in small
  amounts
• Substantial neuron loss
• NF, AP, neuronal loss are more prevalent in
• MTL - Entorhinal cortex, hippocampus, amygdala
• ITC, PPC, PFC

61
Plaques - composed of amyloid beta peptides
Neurofibrillary tangles
62
AD

• Strong genetic component
• Family members 50 chance after 80
• ApoE is the most robust genetic susceptibility
  factor for late-onset AD but is neither necessary
  nor sufficient to cause disease
• Severe gene mutations have been associated with
  early-onset AD (familial)
• amyloid precursor protein (APP)
• presenilins 1 and 2
• Most mutations in the APP and presenilin genes
  increase the production of amyloid beta42, which
  is the main component of plaques

63
AD

• Gene for the amyloid beta precursor protein (APP)
  is located on chromosome 21, and people with
  trisomy 21 (Down Syndrome) who thus have an extra
  gene copy almost universally exhibit AD by
  40 years of age.

64
Treatment

• No cure
• Complicated
• Not clear which symptom is primary
• Amyloid hypothesis amyloid plaques are the
  primary symptoms
• Cause all other symptoms
• Neurofibrillary tangles primary symptom
• Cause all other symptoms

65
Treatment

• Decline in Ach levels
• Cholingeric agonists basically ineffective
• Immunotherapeutic approach
• Amyloid vaccine to reduce plaque deposits and
  improve performance on memory tasks in a
  transgenic mouse model
• Mixed results
• Dangerous side effects

66
Mice Models of AD

• Genes that code for APP and the enzymes involved
  in the processing of APP are good candidates for
  manipulation
• 1st successful genetically modified mouse models
  in AD research were transgenic and increased APP.
• Human APP (hAPP) gene (usually a mutant form
  linked to inherited early onset forms of AD) is
  inserted into the genome.
• If successful, this procedure leads to the
  overexpression of the transgene and,
  consequently, to increased levels of APP
• Amyloid plaques (comparable to human AD), highest
  concentration occurring in MTL
• Robust cognitive disturbances.

67
(No Transcript)