Sheet 6 Flashcards
The basal ganglia (site 4) have several functions, such as:
Controlling and regulating
movement
What is Parkinson’s disease (PD)?
A neurodegenerative disease marked by a hypokinetic movement disorder that is caused by loss of dopaminergic neurons from the substantia nigra
All neurodegenerative diseases are characterized by:
Accumulation of proteins inside the CNS (but they differ in the type of protein and site of deposition) = becomes toxic to the neurons = their death.
What is the most common neurodegenerative disease?
Alzheimer’s
What is the second most common neurodegenerative disease?
Parkinson’s
What is Parkinsonsim?
A clinical syndrome: tremor, rigidity, bradykinesia, and instability.
What is the definition of Parkinsonism?
Any damage of dopaminergic neurons, which project from the substantia nigra to the striatum (control of motor activity).
What happens to the substantia nigra in Parkinson’s in regards to pigmentation?
It’s original brown color loses its pigmentation
Parkinsonism can be induced by:
Drugs such as dopamine antagonists or toxins that selectively injure dopaminergic neurons
What is the pathogenesis of PD?
1) Protein accumulation and aggregation, mitochondrial abnormalities, and neuronal loss in the substantia nigra and elsewhere in the brain.
2) Abnormal protein and organelle clearance due to defects in autophagy and lysosomal degradation.
What is the diagnostic feature of PD?
Lewy body
What are Lewy bodies?
Neuronal inclusions inside the cytoplasm containing α-synuclein, a protein involved in synaptic transmission
Most PD cases are __, but some are __.
Sporadic; autosomal dominant (mutation of α-synuclein gene)
What color do Lewy bodies in a neuron from the substantia nigra stain?
Pink
What do Lewy bodies look like histologically?
Amorphous homogeneous rounded to oval inclusions in the cytoplasm of neurons
What is the morphology of PD?
1) Pallor of the substantia nigra and locus ceruleus. (due to loss of pigmentation)
2) Loss of the pigmented neurons in these regions.
3) Gliosis
4) Lewy bodies in neurons (single or multiple, cytoplasmic, eosinophilic, round to elongated
inclusions)
5) Lewy neurites
6) Immunohistochemical staining for α-synuclein (for subtle lewy bodies).
7) With progression changes can appear in: medulla, pons, amygdala, and the cerebral cortex (+Lewy body dementia LBD).
8) Lewy body dementia LBD
What are Lewy neurites?
Dystrophic neurites that also contain aggregated α-synuclein
What do α-synuclein look like under the microscope?
Appear brown in color
What is Lewy body dementia LBD?
With involvement of the cerebral cortex, there is typically dementia (loss of cognitive features, memory disturbances, behavioral changes) in addition to the movement disorder.
True or false:
Parkinson’s itself does not affect the cognitive features without progression to
the cerebral cortex.
True
The progression of PD is:
1) Gradual (over 10 to 15 years (slow downhill))
2) Eventually produces severe motor slowing or near immobility
3) Death due to aspiration pneumonia or trauma from falls caused by postural instability (gait disorder).
What is the treatment of PD?
1) Initially responds to L-DOPA, but this treatment does not slow disease progression or reverse morphologic findings.(doesn’t affect protein aggregation or neuron loss).
2) Deep brain stimulation
Does L-DOPA help in the long-run?
No; over time, L-DOPA becomes less effective (causes dependence).
What are the symptoms of PD?
1) Tremor
2) Slowed movement (bradykinesia)
3) Rigid muscles
4) Impaired posture and balance
5) Loss of automatic movements
6) Speech changes
7) Writing changes
8) Diminished facial expressions (Masked faces)
9) Stooped posture and balance problems
10) Slow voluntary movement
11) Festinating gait= progressively shortened accelerated steps.
Describe the bradykinesia (slowed movement) of PD.
1) Steps may become shorter
2) Difficult to get out of a chair
3) Drag their feet as they try to walk (Shuffling, festinating gate)
Describe the tremors of PD.
Involuntary shaking, usually at rest and disappears with movement. Begins in a limb, often in the hands or fingers. Patients might rub their thumb and forefinger back-and-forth ( pill-rolling tremor.)
Describe the loss of automatic movements of PD.
Decreased ability to perform unconscious movements, including blinking, smiling (masked face), or swinging arms during walking
Describe the speech changes of PD.
Patients might speak softly, quickly, slur, or hesitate before talking
What is Huntington’s disease characterized by?
1) Hypermotility or mobility
2) Choreiform dancing movements of the whole body (from the head to the limbs and trunk) called chorea
What is the cause of Huntington’s?
Degeneration of the striatum (caudate and putamen) as a result of
protein accumulation.
Huntington’s mode of inheritance is:
Autosomal dominant (NOT sporadic)
What is the progression of Huntington’s?
Gradual, death after an average of 15 years
Do cognitive symptoms occur in Huntington’s?
Yes, early on (forgetfulness and thought and affective disorders, severe
dementia).
What is the pathogenesis of Huntington’s?
CAG trinucleotides repeat expansions in huntingtin protein gene located on 4p16.3 (Polyglutamine) (hundreds of repeats)
What do larger numbers of repeats result in?
Earlier-onset disease
What happens genetically in Huntington’s?
Mutant protein is subject to proteolysis = fragments form large intranuclear aggregates (not in the cytoplasm) = toxic = loss of neurons
What is the age of onset in Huntington’s and what does it depend on?
40-50 years; related to the length of CAG repeats (more repeats = earlier age of onset)
What is the morphology of Huntington’s?
1) Atrophic brain
2) Striking atrophy of the caudate nucleus and the putamen
3) Atrophy of globus pallidus
4) Dilated lateral and third ventricles secondarily (like Alzheimer’s but at small age)
5) Severe loss of neurons from affected regions of the striatum + gliosis
6) Spiny neurons that release γ-aminobutyric acid (GABA), enkephalin, dynorphin, and substance P are especially sensitive, disappearing early.
7) Intranuclear inclusions (aggregates of ubiquitinated huntingtin protein)
