Neuro 67: Motor system pathology

Question 1

Causes/types of Parkinson’s

Answer 1

1. Idiopathic
2. Hereditary
3. Postencephalic
4. toxic (pesticides, herbicides, cycad beans, etc)
5. head trauma (esp. boxers)

Question 2

Alpha-synuclein (park 1)

Answer 2

• early onset
• dominant inheritance
• numerous mutations in the gene that makes alpha-synclein

Question 3

Parkinson’s a mito disease?

Answer 3

• increased reactive oxygen species (ROS)–> increase mito permeability –> causes apop
• ROS also inhibit ubiquitin-proteolysis system –> causes an increase in misfolded proteins –> lewy body formation Increase

Question 4

Ubiquitone-proteolysis system

Answer 4

• gets rid of misfolded proteins

- may be abnormal in PD –> leads to the buildup of Lewy bodies

Question 5

Misfolding of proteins

Answer 5

• Forms inclusion bodies that can aggregate and can cause degredation or apoptosis
• misfolded proteins can have abnormal fctn
• mutations, chaperone abnormalities or free radicals cause misfolding

Question 6

6 Clinical features of classic PD

Answer 6

1. Onset 50-70 yrs in the classic form
2. Tremor at rest, Esp pill rolling
3. Rigidity
4. Bradykinesia (slow moving)
5. Dementia late in some cases
6. Disability in 10-15 hrs

Question 7

Substantia nigra in PD

Answer 7

• loss of the pigmented neurons in the substantia nigra

- this causes an injury to the dopaminergic system

Question 8

Lewy bodies

Answer 8

• seen in PD
• cytoplasmic inclusions in the neurons
• usually 2
• have darker center with a clearer halo
• sometimes have multiple rings

Question 9

Inclusions of lewy bodies

Answer 9

-made of various filaments, including alpha-synuclein

Question 10

MPTP

Answer 10

-toxin that inhibits complex I –> leads to ROS accumulation –> mt membrane permeability –> apoptosis OR the inhibition of the u-p system –> lewy bodies

Question 11

Theoretical Tx of PD

Answer 11

1. Anti-oxidants to combat the ROS –> not successful
2. Co-enzyme Q –> to promote mito integrity
3. Dopamine agonists –> to prevent apoptosis )Pramipexole is in trials right now)

**aim to prevent the cause of the disease

Question 12

Diffuse lewy body disease

Answer 12

• Dementia
• Relatively common
• Parkinsonian features, but more rapid course than classic PD
• find lewy bodies in cerebral cortex and brainstem

Question 13

Progressive supranuclear palsy

Answer 13

• sometimes called atypical PD
• onset 40-60 yrs
• more common in men
• Progressive
• fatal in 5 years

Question 14

Progressive supranuclear palsy: sx

Answer 14

1. Vacant stare
2. Eye mvmnt disorders = vertical gaze palsy
3. Rigidity, tremors, weak, spastic
4. Dysarthria & dysphasia
5. Dimentia

Question 15

Psp pathology

Answer 15

• widespread loss of neurons in the: cerebral cortex, globus pallidus,sub nigra, colliculi, periaqueductal grey, &brainstem nuclei
• NFT found in neurons and glia = Huge, round

Question 16

Globose inclusions

Answer 16

• seen in Psp
• large, bulbous
• neurofibulary tangles
• seen mainly in the brainstem

Question 17

Huntington’s disease: inheritance & genetic

Answer 17

• dominantly inherited
• on chromosome 4
• the gene codes for a polyglutamine region of the protein –> normally there are less than 30 CAG repeats,
• in the disease use will get an increase in the number of glutamine segments –> the more repeats you have = the more severe the disease will be and the earlier the disease onset
• this abnormal protein will, disrupt normal gene functions (ex. Transcription, transport, and transmission) –> the fctn of the normal gene is unknown

Question 18

Huntingtons disease onset and sx

Answer 18

• age 30-50 yrs
• choreiform mvmnts
• personality changes
• dementia later
• average survival is 15 yrs after Dx

Question 19

Huntington disease pathology

Answer 19

• widened ventricles

- atrophy of the BG, ESP caudate nucleus & putamen + cerebral cortex too

Question 20

Huntington and imaging

Answer 20

-can see effects of the disease on imaging, usually the disease is very advanced by the time the disease can be seen

Question 21

Huntington histology

Answer 21

• see atrophy of the small GABA-ergic neurons

- replaced by glial cells = gliosis

Question 22

Huntingtin inclusions

Answer 22

• mutant Huntingtin protein accumulates
• seen within neurons intranuclearly!
• can be seen ONLY with an immuno stain

Question 22

Cerebellar ataxias

Answer 22

• invol tremor

- initiated or made worse by intentional mvmnt

Question 23

Friedreichs ataxia: onset, sx, & prognosis

Answer 23

• onset in older children and young adults
• staggering & ataxic gait
• dysarthria & nystagmus
• decreased vib sensory and prop is diminished
• babinski responses and wkness
• more prevalent in diabetics
• 15 yr survival after Dx

Question 24

Friedreichs ataxia: genetics

Answer 24

- recessive familial - mutation that causes frataxin production regulation to be abnormal - get abnormal synthesis of frataxin, there will be less frataxin - frataxin is on the mito membrane --> so this is prob a mito disease

Question 25

Fried ataxia: histology

Answer 25

-Cerebellar cortical atrophy of All three layers

Question 26

Spinal cord disease in fried

Answer 26

- see long tract disease - damage to post and lat columns - this is where the decreaesed prop and vib sense come from

Question 27

Fried myocarditis

Answer 27

-pts get arrhythmias and CHF

Question 28

Spinocerebellar degenerations

Answer 28

- there is a variety of these that effect both the cerebellum and spinal cord - usually Dom. Inherited - usually caused by increased CAG repeats - the genes involved code for polyglutamine portions of different proteins

Question 29

Motor diseases primary feature

Answer 29

-weakness

Question 30

Motor neuron diseases

Answer 30

- see atrophy in the muscles --> distal first - atrophy is neurogenic --> due to a loss in trophic influence - most cases are idiopathic

Question 31

Sporadic ALS

Answer 31

- sclerosis = gliosis - usually don't know the cause - see TDP-43 inclusions in the cytoplasm

Question 32

TDP-43

Answer 32

- plays a role in sporadic ALS - this protein probably plays a role in preventing apop, so when it is abnormal there will be more apop of neurons and more neurons will be lost! - TDP-43 inclusions seen as Truncated, hyperphosphorylated fragments in the cytoplasm of sporadic ALS pts

Question 33

ALS: onset, clinical features, and prognosis

Answer 33

- onset 30-60 yrs - involves both UMN &LMN - have muscular wkness that usually begins distally w/ atrophy and fasiculations --> BUT facial m. are spared from atrophy!! - have cortical and spinal cord involvement - Progressive course with 3-5 year survival

Question 34

ALS and the spinal cord

Answer 34

- the anterior roots are targeted and become smaller | - pyramidal tracts are diminished = wallerian degeneration

Question 35

ALS histology

Answer 35

- central chromatolysis = reactive change, pre-necrotic change - loss of motor neurons - see ALS-Bunina bodies on the mn.s

Question 36

Bunina bodies

Answer 36

- cyto inclusions - round - red - well defined - autophagic vacuoles - suggests that thaese nare markers for the degenrations of the neurons

Question 37

Poliomyelitis: sx

Answer 37

-acute paralysis: Legs>arms, Sometimes bulbar or respiratory muscles are involved

Question 38

Polio histology

Answer 38

-looks like other viral CNS diseases -see lots of inflam -see: Neuronophagia, lymphocytic cuffing

Question 39

Polio prognosis

Answer 39

- someyptimes do not fully recover becuase there was extensive neuron destruction - Most (80%) patients recover within 6 months --> but pt is usually left with leg wkness

Question 40

Degenerative diseases: what are they and what are they characterized by?

Answer 40

- many are hereditary/genetic - often begin as nerve cell disease - Characterized by: 1. atrophy 2. neuronal loss 3. gliosis

Question 41

Extrapyramidal diseases: 3 sx

Answer 41

1. Random, involuntary, purposeless movements 2. Tremors 3. Rigidity

Question 42

Neuroimaging and PD

Answer 42

- PET scanning shows diagnostic findings - Use 18 fluorodopa and measure brain uptake - Find signal loss in putamen in PD - Test is based on loss of substantia nigra (dopaminergic) projections to corpus striatum--> but these changes are not usually seen until later in the disease, so these tests are not really for Dx

Question 43

Involuntary movements/ataxia: what is it & causes

Answer 43

- Cerebellum is Involved - Causes: 1. Friedrich's ataxia 2. Spinocerebellar ataxias (atrophies) - Often hereditary - Slowly progressive disease

Question 44

Neutrophic Poliomyelitis: onset and cause

Answer 44

- caused by picornavirus - onset=older children and young adults --> This is when virus is neurotropic! - get damage to the LMN b/c the picornavirus gets to the Motor neurons, kills them and causes an encephalitis that involves the sc