Download Parkinson`s Disease

Proseminar in
Biological
Psychology
Lecture 5
Too Much… Too little Dopamine
PD & Schizophrenia
Parkinson’s Disease
First described in 1817
By English MD
James Parkinson
“…involuntary tremulous motion, with lessened
muscular power, in parts not in action and even
when supported, with a propensity to bend the
trunk forwards, and pass from a walking to a
running pace, the senses and intellects being
uninjured.” J. Parkinson
PD: Motor System Disorder
• Chronic
• Progressive
• Non Fatal
-1 to 1.5 million cases in the US
strikes 1 in every 100 over 50
- Equal opportunity disease…
men, women all ethnicities
slightly higher rate among
whites vs blacks
Disease of Aging – onset 55 (idiopathic)
Early Onset: 5-10% diagnosed
Idiopathic
400,000 nigral cells in SN
2,400 cells die each year (Apoptosis)…80yrs X 2,400 = 200,000
…50% cell death = mild symptomology
PD Pts = less than 100,000 cells
So PD accelerated…why?
• environmental?
• genetic?
• Head injury (parkinsonism)
Monozygotic
Dizygotic
Parkinson's Disease
•Lewy body in a substantia nigra neuron
Caused by alpha synuclein & Parkin: gene
responsible for making these proteins suspect 
early onset
Environmental…
Pesticides
Herbicides
Insecticides
Well-Drinking Water
Rural Living
Higher incidence in
agriculture workers….
Environmental…
Metals:
Manganese
Copper
Aluminum
Pathology: Basal Ganglia
Striatum
Dopaminergic
Cell bodies
Nigrostriatal
Pathway
80% die – degeneration of pathway..bingo NO Dopaminergic transmission
Parkinson’s Disease
Disease of the Basal Ganglia
Globus Pallidus
Substantia Nigra
Caudate & Putamen
Sub Thalamic Nuclei
Excites
the
pathway
Inhibits
the pathway
D2
D1
D2 receptors
neurons from putamen fire
excessively…loss of control
of motor function
Excitatory: green -- Inhibitory: red
1. Substantia Nigra axons inhibit the putamen
2. Axon loss increases excitation in Globus Pallidus
3. Globus Pallidus has increased inhibition to Thalamus
4. Then decreased excitation from the Thalamus to Cortex
Symptoms
1. Rigidity
•Muscular stiffness and increased muscle tone
•Patients usually unaware of rigidity, troubled with slowness
•More apparent to doctor than patient
•Cogwheeling – ratchet like movement
2. Hypokinesia & 3. Bradykinesia
•Hypokinesia: inability to initiate a voluntary movement
•Bradykinesia: slowness of movement
•Decrease in:
Eyeblink
Facial expression
Eating and chewing
4.Tremor
Involuntary movement: head, limbs, body
• Most apparent when limb rested
• Increases with stress
• Ceases during sleep
• Decreases with intentional movements
•‘Pill rolling tremor' most prominent in
fingers & hand
•Most bothersome, yet least disabling of
all symptoms
Treatment...
HEY LETS JUST GIVE DOPAMINE!!!
Dopamine doesn’t cross the blood brain barrier….
But levodopa does (l-dopa)!
Phenylalanine
Problems:
1. doesn’t address the cell death
2. in time l-dopa is not effective
(good for early to intermediate stages)
Tyrosine
L- Dopa
Aromatic L amino acid
decarboxylase
•Sinemet: l-dopa+carbidopa (BBB)
Dopamine
l-dopa quickly converted to DA
in PNS  decarboxylase inhibitor
• 75% respond to drug
Selegiline (MAOI)
•Delays Parkinsonian disability and the need for levodopa therapy by 9-12 months
•Inhibits dopamine degradation
•Allows for 20% smaller doses of levodopa
•Exacerbation of levodopa-associated side effects
•Insomnia, postural hypotension
•inhibiting monoamine oxidase-B  more pre-synaptic dopamine
Also…inhibits this enzyme …converts MPTP to MPP+ (bad stuff)
“on-off” of PD
“I need to explain the "on-off"
phenomenon. This Jekyll and-Hyde
melodrama is a constant vexation for
the P.D. patient, especially one as
determined as I was to remain
closeted. "On" refers to the time
when the medication is telling my
brain everything it wants to hear. I'm
relatively loose and fluid, my mind
clear and movements under control.
Only a trained observer could detect
my Parkinson's. During one of my
"off" periods, even the most myopic
layperson, while perhaps not able to
diagnose P.D. specifically, can
recognize that I am in serious
trouble.”
-Michael J. Fox, an excerpt from Lucky
Man
http://www.michaeljfox.org/
Thalamotomy: remove thalamus (M.J. Fox - 1998)
Pallidotomy: remove the globus pallidus
Helps the symptoms of tremor, dyskinesia, rigidity & bradykinesia
-however, irreversible destruction of brain tissue
-Overtime the benefits decline
-May compromise other intact brain processes: speech, vision etc.
New Treatment Strategy…..DBS (deep brain stimulation)
- US Food and Drug Administration recently approved (Jan. 15, 2002)
- Tiny electrodes on the scalp – connecting wire to implanted pulse
generator under the collarbone - 80% reduction of tremor & bradyk.
- can modify stimulation based on severity of symptoms
DBS
•Thalamus
•Globus pallidus
•Sub Thalamic
(best)
Thalamus: tremor, safer then
lesion
•Globus pallidus: dyskinesia
safer than lesion
•Sub Thalamic: improve all
Symptoms
improvement of motor scores
40-60% during “off”
10% during “on”
Epidemiology
• Prevalence ~1%; male = female
Right now over 2 million adult Americans have
schizophrenia
• Seen in all cultures at similar frequency
• Onset usually late adolescence to young adulthood,
earlier in males than females
(reactive: leaving home, loss of parent, 1st sex
experience)
• Increased chance of being born in the winter or early
spring
Schizophrenics have:
• Increased mortality rate from accidents and natural causes:
– life span is shortened by about a decade
– some under-diagnosis of medical illness is present
• ~10-15% suicide; ~50% attempt
–
–
–
–
early in illness and young age
high premorbid function
depression
the latter two often contributing to demoralization
• Illness seems concentrated in urban settings, i.e., it is
somewhat correlated with population density in larger
cities
• Illness seems concentrated in lower socioeconomic classes
(1/3 of homeless)
Subtypes
– Catatonic
• Catatonic behavior dominates (catalepsy-muscle
rigidity/agitation)
• Less common nowadays
– Disorganized (hebephrenic)
• Disorganized speech, behavior, and affect (flat or
inappropriate)
– Paranoid
• Delusions and/or auditory hallucinations
• Not limited to persecutory themes
• Tends to have a later onset and better course
Etiology of Schizophrenia
Genetic Influences
Adoption Studies - Genetic
Implies genetic factors not environmental
Genetics and Family Studies
Etiology of
Schizophrenia
Brain Abnormalities
Hippocampus
Due to virus (Flu) 2nd trimester: adhesion molecules causing pathological migration
Frontal Lobe Issues
Functional brain imaging (PET, rCBF)
• Failure to increase blood flow to the dorsolateral
prefrontal cortex while performing the activation task
of the Wisconsin Card Sorting Test
• Reduced blood flow to the left globus pallidus (an
even earlier finding in the course of illness) suggests
a problem in the system connecting the basal ganglia
to the frontal lobes
• Correlation with severity of disease present
Wisconsin Card Sorting Task
• Subjects are asked to sort each upcoming card on to one of the four piles
(they are not directed but may use shape, color or number). They are told
correct/incorrect. Whichever category they choose is correct for a given
number of categories then is met with an “incorrect” response. Subjects
must “switch sets” to get a correct response. Failure to switch sets is termed
“perseveration”.
• Schizophrenic subjects perseverate relative to normal controls, Green et al,
1992
Ventricles Enlarged
MRI – Discordant
(bigger differences in males - ventricle size)
Post-Mortem Neuroanatomy
Disturbed connection between thalamus and PFC
Serendipity Strikes Again!!!!
1960 – discovery that striatums
(caudate putamens) depleted of Dopamine
Dopamine Hypotheses of
Schizophrenia
• Dopamine
– Schizophrenia due to over activity
Dopamine Antagonist
Clorpromazine (Carlsson, 1963)
- expected DA levels to decrease
-Metabolite increased
-D2 receptor blockers work not
because to much dopamine but
Because to many receptors or too
Sensitive…
Dopamine Hypotheses of
Schizophrenia (revised)
• Dopamine
– Positive symptoms of schizophrenia
attributed to hyperdopaminergic
function (more receptors or increased
sensitivity, etc, D2)
Evidence in Support and Against…
Evidence in Support
•Dopamine hypothesis - weaknesses:
–Does not account for negative symptoms of
schizophrenia
Evidence against DA hypothesis of
Schizophrenia – Glutamate???
• Disorganized thought symptoms of schizophrenia
attributed to hypofunctional glutamate system
• Glutamate antagonists such as PCP and
ketamine mimic disorganized thought, may also
cause psychosis and negative symptoms?