basal ganglia and Parkinson's disease

Question 1

In the basal ganglia system, where do the major inputs come from? where do the major inputs go to? where do the major outputs go to?

Answer 1

inputs come from: cerebral cortex (esp frontal lobe), thalamus (ventral nuclei, medial dorsal nucleus, and intralaminar nuclei), midbrain (substantia nigra pars compacta and ventral tegmental area)
inputs go to: dorsal and ventral striatum, sub thalamic nucleus
outputs go to: thalamus (ventral nuclei, medial dorsal nucleus, and intralaminar nuclei), epithalamus, superior colliculus and pons

Question 2

Where do basal ganglia signals from the thalamus project to?

Answer 2

back to the cerebral cortex! - motor cortex, premotor cortex, supplementary motor cortex, frontal eye fields, prefrontal cortex
and to the striatum!

Question 3

How are the outputs of the dorsal and ventral striatum pathways different? How are their structures different?

Answer 3

dorsal striatum - motor pathways
ventral striatum - motivation pathways
dorsal striatum = caudate nucleus + putamen
ventral striatum = nucleus accumbens septi + olfactory tubercles

Question 4

What neurons receive inputs in the striatum? What neurons are the output neurons in the striatum?

Answer 4

Both are medium spiny neurons

Question 5

What are the two types of medium spiny neurons in the striatum?

Answer 5

Both are GABAergic

1) secretes substance P/has D1 dopamine receptors (neuron is excited by dopamine - D! receptor)
2) secretes enkephalin/has D2 dopamine receptors (neuron is inhibited by dopamine)

Question 6

What fiber tracts transmit signals from the globus pallidus to the ventral thalamic nuclei?

Answer 6

ansa lenticularis and lenticular fasciculus

Question 7

Which type of medium spiny neuron does the direct (striatonigral) pathway use? Which type does the indirect pathway use?

Answer 7

direct - substanceP/D1 receptors

indirect - enkephalin/D2 receptors

Question 8

What are the hallmark signs of parkinsons disease?

Answer 8

Bradykinesia, rigidity, resting tremor, postural instability and slow reflexes, shuffling gait and dementia (only in the late stages)

Question 9

What are the manifestations of bradykinesia in Parkinson’s patients?

Answer 9

impaired rapid alternating movements, poor dexterity, decreased arm swing while walking, handwriting that starts big then gets smaller, lack of facial expressions, infrequent blinking, low volume of voice, drooling because of difficulties swallowing

Question 10

What are the characteristics of the resting tremor in Parkinson’s disease?

Answer 10

asymmetrical onset
pill rolling
disappears while asleep

Question 11

What symptoms of parkinson’s often precede motor symptoms?

Answer 11

mood disorders (depression, cognitive decline), restless leg syndrome

Question 12

What are the non-motor symptoms in parkinson’s disease?

Answer 12

autonomic symptoms: erectile dysfunction, constipation, orthostatic hypotension, urinary retention
REM sleep behavior disorder (patients are not paralyzed in REM sleep so they act out their dreams and hurt themselves/others)
anosmia
mood disorders

Question 13

What are Lewy bodies? What diseases are they associated with?

Answer 13

eosinophilic nuclear inclusions of alpha-synuclein and ubiquitin. Found in the substantia nigra. Associated with Parkinson’s disease and Lewy Body disease/dementia

Question 14

Why is carbidopa always given with levodopa? What is the combination of these two drugs called?

Answer 14

Levodopa is converted to dopamine in both the brain and the blood. In the periphery, dopamine has a strong emetic effect. Carbidopa is an inhibitor of LDOPA decarboxylase but it cannot cross the BBB. Thus, carbidopa prevents LDOPA from being broken down into dopamine in the blood while still allowing LDOPA to be converted to dopamine in the brain. This drastically reduces vomiting.
Sinemet = carbidopa + LDOPA

Question 15

Besides LDOPA, what are the classes of drugs that treat Parkinson’s? What is their mechanism of action?

Answer 15

Dopamine agonists (D2) - Rotigotine - transdermal patch of dopamine agonists
MAO-B inhibitors - prevents enzymatic breakdown of dopamine in the synapse. (Selegiline, rasagiline)
COMT inhibitors - prevents enzymatic breakdown of dopamine in the synapse
Amantadine - also used to treat the influenza virus, don’t know why it works. Reduces dyskinesias.
Anticholinergics - for tremor and dystonia
Deep brain stimulation
botulin toxin - used as injections into parotid gland to stop drooling

Question 16

What are the side effects of the drugs that treat Parkinson’s?

Answer 16

nausea and vomiting
orthostatic hypotension
dyskinesias
psychosis
sleep attacks
compulsive behaviors like gambling, hypersexuality, shopping and eating

Question 17

How can you distinguish between Parkinson’s disease and atypical parkinson’s? Besides PD and AP, what should you also keep on the differential?

Answer 17

True PD will respond to L-dopa
Differential = stroke, tumor in basal ganglia, normal pressure hydrocephalus, managnese toxicity, carbon monoxide poisoning, wilson’s disease

Question 18

What are the Parkinson’s mimicking degenerative disorders?

Answer 18

Lewy body disease
multi-system atrophy
progressive supranuclear palsy (PSP)
cortical basal ganglionic degeneration

Question 19

How is Lewy Body disease distinct from Parkinson’s? How is is similar?

Answer 19

Differences: Early dementia; early cognitive decline with wide fluctuations in cognitive ability from day to day; prominent visual hallucinations
Similarities: Lewy bodies on histology; REM sleep behavior disorder; muscle stiffness; shuffling gait; reduced arm swing, cog wheeling, drooling, low speech volume

Question 20

What are the clinical manifestations of multi-system atrophy?

Answer 20

Early autonomic dysfunction: orthostatic hypotension, incontinence, ect
symmetrical parkinsonism
forward flexed spine while standing but not while lying down! (camptacormia)
rapid progression

Question 21

What are the clinical manifestations of progressive supra nuclear palsy?

Answer 21

The "toppling disease"
Early postural instability with falls
symmetric onset
NO tremor
vertical gaze palsy
frontal disinhibition leads to inappropriate emotional responses

Question 22

What are the clinical manifestations of cortical basal ganglionic degeneration?

Answer 22

rapid progression
NO tremor
“alien limb” - patients are unaware of one limb
myoclonus
cortical involvement leads to emotional incontinence (outbursts of emotions with no real feeling behind them)
apraxia: inability to make voluntary movements despite normal strength
mirror movements

Question 23

What are the manifestations of decreased postural stability?

Answer 23

failed pull test
turning body on block
needs two tries to get out of a chair without arms

Question 24

What is the pathogenesis of Hungtinton’s disease?

Answer 24

Mutant Huntington proteins accumulates in D2/enkephalin medium spiny neurons in the dorsal striatum (esp caudate nucleus). Lead to the death of these neurons and inhibition of the indirect pathway. Thus, the direct pathway predominates over the indirect pathway so there is a net disinhibition of the thalamus and a increased excitatory output to the cortex -> increased movement. Eventually involves the direct pathway too.

Question 25

What is dystonia?

Answer 25

When the basal ganglia is sending too many excitatory signals to the muscles. Agonists and antagonists are trying to flex at the same time so the body becomes very rigid.
Asymmetric. Can make the dystonia get better if you move to the “good side”

Question 26

How does dopa-responsive dystonia present?

Answer 26

starts as leg dystonia and becomes generalized. Affects children in the first decade. It becomes worse later in the day. It has a very good response to Ldopa.
Non-degenerative! Mutation is in the dopamine synthesis pathway - doesn’t kill cells.

Question 27

What is the cause of tardive dystonia? What are the symptoms of tardive dystonia?

Answer 27

treatment with drugs that block dopamine receptors (antiemetics, antipsychotics).
Symptoms include lip-smacking, lip pursing, tongue protrusion, jerky retrocollis (chin up, head back), any form of dystonia

Question 28

What are the characteristics of a tic?

Answer 28

Patient feels an urge, performs the movement then feels a sense of resolution
Suppressible!

Question 29

What is the initial factor that brings on rapid-onset dystonia parkinsonism?

Answer 29

Begins abruptly in childhood or early adult life precipitated by severe physiologic or psychologic stress. Patients develop bradykinesia with dystonia in the face, hands, and legs. Face can get the risus sardonicus smile

Question 30

What are the treatments for tics? In kids? In adults?

Answer 30

Most of the time no treatment is necessary because they are benign.
Habit reversal therapy
alpha agonists (clonidine an guanfacine) for kids. Lower BP too much in adults
dopamine-blocking agents - risperidone

Question 31

Wilson’s disease is one of the “Great Imitators.” What is the pathogenesis of Wilson’s’? When would you suspect Wilson’s disease? What is the gold standard test for Wilsons?

Answer 31

Genetic mutation in the copper transporting enzyme so copper builds up in the liver, eye and brain.
Liver symptoms and neuro/psych symptoms in a child to young adult. Check for Kaiser Fleischer rings
24 hour urine copper test

Question 32

What adjunctive treatments are used to treat tremor in parkinson’s disease?

Answer 32

muscarinic antagonists like trihexylphenidyl and benzotropine because it is thought that the tremor