Disorders and Damage

1
Disorders and Damage

• Degenerative disorders
• Parkinsons disease
• Alzheimers disease
• Neurological damage
• Stroke
• Developmental disorders
• Autism
• Psychological disorders
• Schizophrenia

2
Parkinsons disease

• Major degenerative disease resulting from
  degeneration of dopamine-producing neurons in the
  substantia nigra
• Nigrostriatal system

3
Parkinsons disease symptoms

• Symptoms are primarily motor deficits
• Muscular rigidity
• Slowness of movement
• Resting tremor
• Postural instability
• Cognitive deficits appear in late stages of PD
• Speech is impaired
• Dementia is seen in late stages of PD in 25 of
  patients

4
Parkinsons disease - Lewy bodies

• Damage results from accumulation of abnormal
  proteins in the neurons
• Lewy bodies are found in remaining dopamine cell
  bodies
• Protein core made up of misfolded a-synuclein

5
Parkinsons disease causes

• Most cases of PD are idiopathic - no identified
  cause
• Genetic mutations, toxins, infection, head trauma
  and faulty metabolism functions have been
  identified as causes of some cases

6
Parkinsons disease causes

• Genetic mutations have been identified in some PD
  patients
• Mutations result in misfolded a-synuclein and/or
  failure to destroy damaged proteins
• Specific toxins have been linked with PD
• MPTP
• Rotenone, paraquat, PCBs and other agricultural
  and manufacturing chemicals

7
Parkinsons disease causes

• Head trauma appears to be linked to later
  development of Parkinsons-like symptoms
• Risk is correlated with extent of head damage
• Pugilistic Parkinsons syndrome - results from
  repeated head trauma and concussions
• Produces symptoms characteristic of PD

8
Treatment of Parkinsons disease

• Initial treatment is L-DOPA (DA precursor)
• L-DOPA works as long as there are surviving
  dopamine neurons to make the NT
• Other treatments are being studied and used,
  including
• Stem cell transplants
• Pallidotomy
• Deep brain stimulation

9
Treatment of Parkinsons disease

• Stem cell transplant
• Dopamine cells, taken from fetal substantia nigra
  or cultured from omnipotent stem cells
• Inserted into substantia nigra of PD patients
• Most cells die upon transplantation, a few graft
  into the host and make dopamine
• Research is still in early stages

10
Treatment of Parkinsons disease

• Pallidotomy
• Removal of inhibitory region of globus pallidus
• Relieves rigidity and motor
• impairments, returns motor
• cortex activity to normal

11
Treatment of Parkinsons disease

• Deep brain stimulation
• Stimulates the subthalamic nucleus in order to
  remove motor inhibition
• Relieves motor impairments and tremor
• Fewer side effects than pallidotomy

12
Alzheimers disease

• Progressive degenerative disease
• Most common form of dementia
• Progresses through 5 stages, characterized by
  cognitive losses
• Stage 1 Characterized by absentmindedness
• Stage 2 Confusion becomes more profound,
  noticeable losses in memory and concentration

13
Alzheimers disease

• Stages of AD (contd)
• Stage 3 Memory is severely diminished
• Stage 4 Memory and personality are mostly gone
• Stage 5 All language, emotion and most motor
  abilities are gone

14
Alzheimers disease

• Neural damage is seen throughout the cortex,
  limbic system and brain stem
• Deficits are seen in most systems and functions

15
Damage in Alzheimers disease

• Correlated with the presence of two abnormal
  protein accumulations
• Neuritic plaques neurofibrillary tangles

• Neurofibrillary tangles
• Twisted filaments of tau proteins in degenerating
  neurons

16
Damage in Alzheimers disease

• Neuritic plaques
• Extracellular deposits consisting of a dense core
  of ß-amyloid protein, surrounded by degenerating
  neurons
• ß-amyloid occurs in short and long forms
• Alzheimers brains have too much long form
  ß-amyloid

17
Causes of Alzheimers disease

• Some familial forms of AD have been identified
• Most cases are NOT hereditary
• Believed to be linked to injury, infection,
  drug/alcohol abuse and exposure to toxins
• Research is examining these possibilities

18
Causes of Alzheimers disease

• ALL damage seen in AD results from abnormally
  high amounts of ß-amyloid plaques in the brain
• ß-amyloid plaque appears to be the cause of
  damage
• Twisted tau proteins are an effect of the
  disease, not a cause

19
Treatment for Alzheimers disease

• All AD treatments are in preliminary stages of
  development
• Nonsteroidal anti-inflammatory (NSAID) drugs
  reduce the progression of cognitive loss

20
Treatment for Alzheimers disease

• Vaccine against ß-amyloid is being developed
• In AD mice, the vaccine suppresses development of
  ß-amyloid plaques
• In humans, patients generated antibodies against
  ß-amyloid and showed reduced cognitive decline

21
Stroke

• Stroke damage occurs when an area of the brain is
  deprived of blood flow (ischemia)
• Results in lack of oxygen and glucose
• Two major types of stroke
• Hemorrhagic
• Obstructive

22
Hemorrhagic stroke

• Results from bleeding into the brain
• Occurs when a weakened blood vessel ruptures
• Blood causes direct damage
• Lack of blood to the area causes extensive damage

23
Obstructive stroke

• Results from obstruction of a blood vessel,
  interrupting blood flow to the brain
• Embolism
• Thrombosis

24
Obstructive stroke

• Embolism - piece of material that travels through
  the vascular system and becomes lodged in a small
  artery
• Blocks blood flow to the brain
• Material that has formed elsewhere in the body

25
Obstructive stroke

• Thrombosis - pathological blood clot
• Forms in a blood vessel, cutting off blood flow
• Results in ischemic damage
• Can happen anywhere in the body

26
Transient Ischemic Attack

• a.k.a. Mini-stroke
• A brief, stroke-like episode resulting from a
  temporary disruption of blood flow to the brain
• Symptoms include brief neurological dysfunction,
  reflective of the site of damage

27
Transient Ischemic Attack

• Single TIA produces very small amount of damage
• Patients are likely to experience repeated
  occurrences

28
Cause of ischemic damage

• Loss of oxygen and glucose ? rapid loss of cell
  functions, including Na/K pump
• Resting membrane potential is no longer
  maintained
• Na enters and cells depolarize
• Depolarization releases glutamate, causing
  further depolarization of cells in the region
• Calcium floods cells
• Excess sodium and calcium in the cell begin a
  cascade of toxic events resulting in cell death
• Immediate cause of neuronal death excessive
  glutamate flooding the synapse
• Produces excitotoxic damage

29
Cause of ischemic damage

• Following the initial excitotoxic lesion, damage
  spreads to the surrounding area
• Blood in the area will kill other neurons
• Excess glutamate will spread damage
• Free radicals, released by damaged tissue, cause
  oxidative damage in surrounding area
• Inflammation exerts pressure on surrounding tissue

30
Treatment following stroke

• Minimizing further damage
• Circulation to the brain must be reestablished
• Medications used to dissolve clot
• Research is exploring treatments to prevent the
  spread of damage

31
Treatment following stroke

• Recovering lost function
• Physical speech therapy can help overcome
  losses
• Research in animals and humans - exercise,
  sensory stimulation and use of damaged limbs can
  recover some motor function
• Constraint-induced movement

32
Autistic spectrum disorders

• Pervasive developmental disorders identified by
  severely impaired social relationships and
  communication
• Autism
• Aspergers syndrome
• Rhett syndrome
• Childhood disintegrative disorder

33
Autism symptoms

• Affective abnormalities
• Behavioral abnormalities
• Cognitive abnormalities

34
Brain pathology in autism

• Abnormal brain volumes
• Increased grey matter
• Decreased grey matter
• Decreased white matter connecting distal brain
  regions

35
Brain pathology in autism

• Impaired activation of the fusiform gyrus
• Facial recognition area

36
Brain pathology in autism

• Brainstem nuclei small or missing
• Facial nucleus of the brainstem
• Motor neurons decreased by 90
• Superior olivary complex
• Absent

37
Possible causes of autism

• Genetic heritability
• 70 of monozygotic twins are concordant
• 2-3 of siblings are concordant
• Numerous genes have been implicated
• Prenatal infection
• Rubella
• Herpes encephalitis
• Tuberous sclerosis

38
Possible causes of autism

• Early brainstem injury
• Brainstem nuclei fail to develop
• Result of assault during day 20-24 of
  development, as neural tube is closing
• Prenatal infection, teratogen exposure, or
  genetic abnormalities may cause these injuries
• No evidence of childhood immunizations
  causing/influencing autism

39
Schizophrenia

• Serious mental disorder, characterized by
  distinct symptoms
• Positive symptoms
• Thought disorder
• Hallucinations
• Delusions
• Negative symptoms
• Flat affect
• Lack of motivation
• Decline in speech and communication

40
Neural characteristics of schizophrenia

• Dopamine hypothesis
• Positive symptoms may result from an excess of
  dopamine activity in the mesolimbic system
• DA release is higher in schizophrenic patients
• DA agonists can cause these symptoms
• DA antagonists reduce the positive symptoms
• DA activity may affect
• Attentional processes in the nucleus accumbens
• Delusions via activation of the amygdala

41
Neural characteristics of schizophrenia

• Glutamate hypothesis
• Symptoms may be linked to underactivation of
  glutamate receptors
• Schizophrenia linked to a gene for a faulty
  glutamate receptor
• Antagonists (PCP, ketamine) produce similar
  symptoms
• Agonists decrease symptoms

42
Neural characteristics of schizophrenia

• Brain abnormalities
• Negative symptoms may be caused by developmental
  abnormalities in the brain
• Enlarged ventricles and decreased cortical grey
  matter
• Loss of cortical matter occurs rapidly, in
  adolescence

43
Neural characteristics of schizophrenia

• Decreased metabolic activity in the frontal
  cortex results in hypofrontality
• Decreased frontal cortex function
• Results in negative symptoms
• Results in increased DA release in the nucleus
  accumbens
• Hypofrontality may either cause or support an
  overactive mesolimbic DA system

44
Causes of schizophrenia?

• Schizophrenia has been linked with prenatal
  factors
• Prenatal exposure to a virus
• Flu epidemic
• Flu season
• Dense populations
• Rubella, toxoplasmosis, influenza
• Prenatal maternal stress
• Rh incompatibility
• Being a 2nd Rh-positive offspring

45
Causes of schizophrenia?

• Any or all prenatal factors may result in brain
  abnormalities
• Symptoms of schizophrenia do not appear until
  adolescence
• Environmental or developmental factor must
  influence onset
• Discordant rates of schizophrenia among
  monozygotic twins supports the precipitating
  stimulus theory
• Environmental stressor? Developmental occurrence?

46
Treatment

• Antipsychotic drugs
• Typical antipsychotics
• Dopamine antagonists
• Chlorpromazine (Thorazine)
• Haloperidol (Haldol)
• Pimozide
• Atypical antipsychotics
• Work at a variety of post-synaptic receptors
• Clozapine
• Aripiprazole (Abilify)
• Psychotherapy
• Cognitive-behavioral therapy