Disorders Affecting Motor Function (Physiology) - Block 1

Question 1

What is Parkinsons?

Answer 1

Progressive degenerative CNS disorder and disorder of basal ganglia function

Question 2

What is the mechanism of basal ganglia function disorder?

Answer 2

Progressive destruction of the nigrostriatal pathway leads to the reduction of strial dopamine concnetration

Question 3

What is the clinical syndrome of parkinsonism?

Answer 3

Tremors, akinesia/bradykinesia, rigidity, postural instability

Question 4

What is primary parkinsonism?

Answer 4

1. Idiopathic
2. Dopamine depletion -> degeneration of the dopamine nigrostriatal system
3. Sx due to dx

Question 5

What is secondary parkinsonism?

Answer 5

Sx occur due to cause other than dx:
1. Head trauma
2. Toxins
3. Metabolic disorders
4. Encephalopathy
5. Brain tumors’
6. Drugs

Some cases can be reversed

Question 6

What are the RF of developing PD?

Answer 6

1. Increased age
2. Male
3. Environmental exposure to toxins
4. Family hx
5. Genetics

Question 7

What is the difference between autosomal recessive and dominant forms of PD?

Answer 7

Recessive: milder sx
* mutations is due to genetic code of protein, parkin (early onset of PD)

Dominant: rare and associated with increased a-synuclein and Lewy bodies

Question 8

What is the function of parkin?

Answer 8

Acts as an enzyme in the Ub-conjugating system that targets defective and abnormally folded proteins for destruction.
* Loss of normal parkin cause abnormal proteins to aggregate -> neurodegenerative changes

Question 9

The risk of PD is inversely related to?

Answer 9

1. Cigarette smoking
2. Caffeine
3. High serum urate

Question 10

How does PD cause brain abnormalities?

Answer 10

1. Degeneration of nigrostrial dopamine neurons
2. Loss of pigmented substantia nigra neurons (neuromelanin)
3. Some residual nerve cells become atrophic and contain Lewy bodies

Question 11

What is the most prominent sign of PD?

Answer 11

Progressive depletion of presynaptic dopamine in the basal ganglia, substantia nigra (SN), and pathwaysto the corpus striatum (caudate nucleus and putamen)

Question 12

What is the consequence of progressive dopamine depletion?

Answer 12

Abnormal firing patterns that increase inhibition of the thalamus and reduce excitatory input to the motor cortex

Question 13

What is proteolytic stress?

Answer 13

Unwanted proteins accumulate in cells interfering with UPS and inducing cytotoxitity

Question 14

What are Lewy bodies?

Answer 14

Inclusions or abnormal protein filled neurons associated with proteolytic stress

Question 15

What is in lewy bodies that misfold and aggregrate proteins?

Answer 15

alpha (a)-synuclein

Question 16

What is oxidative stress?

Answer 16

ROS accumulation in cells -> toxicity and cellular damage

Question 17

What causes oxidative stress in PD?

Answer 17

ROS are generated by oxidation of dopamine within cells of the SN

Question 18

Describe how a heathy body copes with oxidative stress?

Answer 18

1. α-synuclein facilitates endocytosis of transferrin receptor and iron-bound holo-transferrin.
2. A cytoplasmic labile iron pool is tightly maintained by ferritin to enable ferroprotein function, including dopamine production by tyrosine hydroxylase (TH).
3. α-synuclein facilitates multiple steps in synaptic dopamine release and repackaging

Question 19

Describe how a PD body copes with oxidative stress?

Answer 19

1. Oxidation and phosphorylation of α-synuclein impair transferrin receptor-mediated iron import
2. Combined with an age-dependent diminution in the iron storage capacity of ferritin, this elevates the labile iron pool, which reacts with free dopamine to produce ROS.
3. Free dopamine is also elevated due to impaired dopamine packaging
4. Oxidation and phosphorylation of α-synuclein is associated with Lewy pathology deposition, exacerbating nigral oxidative stress.

Question 20

What is the mitochondrial dysfunction theory?

Answer 20

Decrease in mitochondrial complex activity contributes to the development of PD

Question 21

How does PD cause inflammation?

Answer 21

Overactivation of microglia:
* leads to excess production of neuortoxic facotors -> neurodegeneration
* This accumulation triggers the activation of glial cells and the freeing of proinflammatory cytokines

Question 22

What is the most visible sign of PD?

Answer 22

Tremor

Question 23

What are motor sx of PD?

Answer 23

1. Tremors (pill-rolling)
2. Rigidity: increased muscle stiffness and tone (cogwheel-type or ratchet-like movements)
3. Bradykinesia
4. Postural instability (feeling of imbalance, classic sx)

Question 24

What is cogwheeling?

Answer 24

Slight hesitations during movement that produce a stop-and-go effect

Question 25

What is bradykinesia?

Answer 25

Slowing of voluntary muscle activity * Festination: Acceleration while walking in an effort to “catch up”; result of flexed posture and postural instability. * Freezing of gait: sudden and transient inability to move

Question 26

What are physical sx of PD?

Answer 26

1. Fatigue 2. Sleep disturbances 3. Olfactory dysfunction 4. Pain 5. Autonomic dysfunction

Question 27

What are potential neuropsychiatric sx of PD?

Answer 27

1. Cognitive dysfunction 2. Deficit in frontal labe executive function 3. Dementia 4. Deficit in visuospatial discrimination 5. Deficit in memory retrieval 6. Psychosis 7. Mood disorder 8. Depression/Axiety 9. Hallucinations

Question 28

How do we stage sx of parkinsons?

Answer 28

Hoehn and Yahr Staging of Parkinson Disease scale Unified Parkinson Disease Rating Scale

Question 29

What is MS?

Answer 29

A chronic, inflammatory, demyelinating (white matter), and axonal degenerative disorder of the CNS **inflammatory autoimmune disease**

Question 30

What are the risk factors of MS?

Answer 30

1. 20-50 YO 2. Women 3. Caucasians of northern descent 4. Live farther from the equator 5. People with the human leukocyte antigen **HLA-DR2** haplotype are particularly susceptible

Question 31

What are the triggers of MS?

Answer 31

1. Viral infection 2. Environmental factors 3. Genetic predisposition

Question 32

Describe plaque formation of MS?

Answer 32

1. A trigger sets off an inflammatory process, and the protective blood-brain barrier (BBB) is disrupted 2. Inflammatory T cells, B cells, and macrophages enter the brain and attack myelin. 3. Demylination of neurons cause conduction abnormalities 4. Axonal degen and atrophy of both gray and white matter

Question 33

What is a myelin?

Answer 33

Protein substance that coats the axon of a neuron and increases conduction velocity; produced by oligodendrocytes in the CNS.

Question 34

What are some of the causes of MS?

Answer 34

1. Lesions 2. Plaques

Question 35

What are the stages of lesions?

Answer 35

**First:** involves the sequential development of small inflammatory lesions **Second:** lesions extend and consolidate; demyelination and gliosis (scar formation) occur

Question 36

Describe the types of progression of MS?

Answer 36

**Relapsing-remitting multiple sclerosis (RRMS):** patient remains stable or near but then transitions to secondary progression MS **Secondary progressive multiple sclerosis (SPMS):** Gradually worsening sx w/ or w/o occassional relapses, minor remissions, and plateaus **Primary progressive multiple sclerosis (PPMS):** Progressive deficit from the time of onset with occassional plateaus, temporary improvements, or acute relapses **Progressive-relapsing multiple sclerosis (PRMS):** Gradual neurologic deterioration from the onset of sx but with subsequent superimposed relapses

Question 37

Identify some of the areas MS affects?

Answer 37

**Optic nerve:** visual field. **Corticobulbar tracts:** speech and swallowing. **Corticospinal tracts:** muscle strength. **Cerebellar tracts:** gait and coordination. **Spinocerebellar tracts:** balance. **Medial longitudinal fasciculus:** conjugate gaze function of the extraocular eye muscles. **Posterior cell columns of the spinal cord:** position and vibratory sensation.

Question 38

What is restless legs syndrome?

Answer 38

Strange sensation in the legs and an accompanying need to move the legs when resting or lying still

Question 39

What are the RF of RSL?

Answer 39

1. Diabetes 2. Pregnancy 3. Uremia 4. Iron def 5. Anemia 6. Obese 7. Caffeine 8. Smoking 9. Sedetary 10. Meds

Question 40

What is the difference between primary and secondary RLS?

Answer 40

**Primary:** hereditary component **Secondary:** people with condditions that predispose them to iron-def anemia

Question 41

What are the causes of RLS?

Answer 41

Involves homeostatic mechanisms that regulate the influx and efflux of iron from cells of the CNS: * Cerebrospinal fluid ferritin are lower with RLS * Iron is involved in dopaminergic transmission in the CNS and cofactor of tyrosine hydroxylase (rate-limiting steps of dopamine synthesis)

Question 42

How does RLS cause both sleep and motor sx?

Answer 42

Low levels of iron in the brain: 1. Reduced tyrosine hydroxylase and dopamine production 2. decrease in the dopamine transporter (DAT). 3. number of transferrin receptors is decreased 4. Insufficient amount of iron regulatory protein 1 (IRP1), which represses degradation

Question 43

What are sx associated with RLS?

Answer 43

1. Urge to move legs coupled with unpleasant sensations 2. Rest provokes sx 3. Getting active relieves sx 4. Evening and night worsen sx