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Brain PD > Week 3 Part 2 > Flashcards

Week 3 Part 2 Flashcards

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1
Q

What is neuromuscular disorder?

A
  1. Very broad term that encompasses many diseases and ailments that impair the functioning of muscles
    - directly: pathologies of the voluntary muscle
    - indirectly: pathologies of the nerves or neuromuscular junctions
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2
Q

What are the list of pathologies that affect the motor cells?

A
  1. Amyotrophic lateral sclerosis (ALS)
  2. Progressive bulbar palsy (PBP)
  3. Progressive muscular atrophy (PMA)
  4. Primary lateral sclerosis (PLS)
  5. Flail arm/leg syndromes
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3
Q

Where can the pathologies be found?

A
  1. More rostrally

2. At the level if brainstem in the cortex

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4
Q

Disorder of muscle

A
  1. Inflammatory

2. Degenerative

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5
Q

What does the normal motor function depend on?

A
  1. Transmission of signals from the brain to brainstem/spinal cord by upper motor neuron
  2. And from there to skeletal muscle by lower motor neurons
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6
Q

What does the white matter contain?

A
  1. The neuron axon which travel through the brain
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7
Q

Where will motor neuron pass through?

A
  1. The internal capsule situated at the thalamus and the basal ganglia
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8
Q

What does the upper motor neuron transmit?

A
  1. Transmits information from brain to the spinal cord
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9
Q

Where does the lower motor neuron transmit information?

A
  1. From the brainstem/spinal cord to the skeleton muscles
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10
Q

What causes upper motor neuron lesion?

A
  1. Stroke
  2. Infection
  3. Tumour

Damage to brain

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11
Q

What causes Lower motor neuron?

A

Injury to the white matter of the spinal cord

Any damage along the tracts

  1. Injury to the axons leaving the spinal cord
  2. Injury to the ventral gray matter of the spinal cord
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12
Q

What are the signs elicited on examinations depend on?

A
  1. What area of the motor pathway is affected - which sides of the brain
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13
Q

UMN

A
  1. Minimal muscle atrophy

2. Weakness

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14
Q

What is Amyotrophic lateral sclerosis (ALS)?

A
  1. A group of rare neurological diseases that mainly involve the nerve cells responsible for controlling voluntary muscle movement
  2. The disease is progressive - symptoms get worse over time
  3. Both the LMN and UMN degenerate and die - stop sending messages to the muscle
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15
Q

What are early symptoms of ALS?

A
  1. Muscle weakness or stiffness

2. Individuals lose their strength and the ability to speak, eat, move and even breathe

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16
Q

Genetics of MND

A
  1. Occurred the last 10 years
  2. Association with dominant variants at several genetic loci
  3. Variants in the same gene are thought to contribute to the genetic etiplogy of both familial and apparently sporadic cases
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17
Q

What are the main contributors in the UK for the genetics of MND?

A
  1. Expansion of intronic hexanucleotide repeat in C9orf72 and missense variants in SOD1 and TARDBP
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18
Q

What are the processes occurring in the genetics of MND?

A
  1. Oxidative stress
  2. Mitochondrial dysfunction
  3. Axonal transport
  4. RNA processing
  5. Glutamate excitotoxicity
  6. Cytoskeletal disorganisation
  7. Protein aggregation
  8. Apoptosis
  9. Inflammatory stress
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19
Q

What can ALS be?

A
  1. Familial in nearly 10% of cases
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20
Q

Genetic factors in ALS

A
  1. Range from a highly penentrant ALS-linked gene variants to sequence variants with seemingly limited impact on disease susceptibility
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21
Q

What are the possible causes of sporadic ALS?

A
  1. Oxidative stress
  2. Mitochondrial dysfunction
  3. Abnormalities Of the immune system
  4. Glutamate toxicity
  5. Toxic exposure s
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22
Q

What is familial ALS?

A
  1. More than one occurrence of the disease in a family
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23
Q

What is sporadic ALS?

A
  1. There is no known history of other family members with the disease
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24
Q

What are mutations of some of the genetic causes of ALS?

A
  1. SOD1
  2. TARDBP
  3. FUS
  4. VCP
    - generation of rodent models of the disease
25
Q

What is the first gene shown to be mutated in FALS?

A
  1. SOD1
    - chromosome 21
  • first identified causes of autosomal dominant FALS in 1993
26
Q

How can SOD1 cause ALS?

A
  1. Loss of dismutase activity
27
Q

What does SOD1 cause,

A
  1. Degeneration
  2. At the level of spinal cord motor neurone pool
  3. This detrimental effect may be accelerated by environmental stressors
28
Q

What can mild compression SCI and over-expression of the G93A-SOD1 gene in rat induce?

A
  1. Time-dependent transcriptional regulation of the same molecular responses modulating:
    - oxidative stress
    - apoptosis
    - inflammation
    - membrane ion transport
    - neurofilament homeostasis
29
Q

What does G93A-SOD1 toxicity show to increase?

A
  1. Vulnerability of motor neurons and muscles to sciatic nerve injury
    - reducing the post-injury motor unit survival
    - impairing muscle contractile characteristics
30
Q

What are the gross neuropathologival features in ALS

A
  1. No gross abnormalities are observed
  2. The spinal cord reveals atrophy of the anterior nerve roots
  3. Some cases exhibit atrophy of the precentral gyrus
  4. White matter reduction is also observed
31
Q

What are the microscopic neuropathological features of ALS?

A
  1. Neuronal and axonal loss
  2. Loss of myelinated axons in lateral and anterior columns of the spinal cord
  3. Decrease in size of the anterior horn of the spinal cord - myelin stains- luxol fast blue
  4. Loss of large motor neurons in the anterior horn of spinal cord
32
Q

What are other pathological features of ALS?

A
  1. Vacuolization
  2. Large empty spaces near Neurons
  3. Spongiosis
33
Q

The nonneuronal cell involvement

A
  1. Both microglial and astrocytic proliferation
34
Q

What does T2 weighted and proton-density-weighted MRI show?

A
  1. Hyper intensive or Hypointense signals at the corticospinal tract
35
Q

What does FLAIR sequences increase the sensitivity of?

A
  1. MRI to detect cortical and subcortical tissue changes
36
Q

What does the T1-weighted images show?

A

The corticospinal tract at capsules interna was hypointense

37
Q

What are the pathology of motor neuron?

A
  1. Clinically heterogenous
  2. Poor survival
  3. Gastrostomy
  4. Family history
38
Q

What is the function of SOD1 gene?

A
  1. Ubiquitous

2. Detoxification - get rid of free radicals

39
Q

What does dysfunction of SOD1 gene cause?

A
  1. Motor cell death
40
Q

SOD1 gene mutations: genotype vs phenotype

A
  1. 2% of patients
  2. Over 150 missense mutations
  3. D90 mutations: recessive + dominant
  4. A4V - 91% penetrance
  5. H46R -18 years survival
  6. A89V inxomplete penetrance and variable age onset
41
Q

What is the SOD1 protein

A
  1. 153 as homodimer protein
  2. Spans 11kb DNA, contains 5 exams
  3. Copper (activity) and zinc (stabilisation)
  4. Highly conserved and constitutively expressed I. All eucariotic cells
42
Q

What does the motor neuron disease lead to?

A

A more widespread cortical environment and therefore the borderline between condition like fronto-temporal dementia (cortical)

43
Q

What will a lot of patients with MND have?

A

signs of fronto-temporal dementia

44
Q

What is a fronto-temporal dementia?

A

A cognitive impairment which is related to behavioural abnormalities

45
Q

What is the clinical features of ALS?

A
  1. rapidly progressive

2. weakness, muscle wasting, pyramidal signs, bulbar dysfunction, respiratory failure

46
Q

What is prevalence of ALS?

A

2-6 per 100,000

47
Q

What is the incidence of ALS?

A

1.2-2/100,000

48
Q

What makes a motor cell sensitive to damage?

A

The presence of a very high energy requirement

49
Q

SOD1 gene

A

» Key protein which is about 2% of cytosolic protein – important structure for biology

50
Q

What is ALS?

A

» ALS is not a pathology of the motor cells – it is a systemic pathology

51
Q

What is animal models?

A

biological platform to understand what is happening at the tissue level or what is happening before the disease starts

52
Q

Where are 9 pathological changes that occurs when mice is functional?

A
  1. Vacuole system
  2. Golgi
  3. ER
  4. Mitochondria
53
Q

What is linked to the development of ALS?

A

TDP-43

54
Q

What is mitochondria susceptible to?

A

insults of:

  1. excitotoxicity from glutatamate
  2. Oxidative stress from free radicals
55
Q

What is the Axonal transport in ALS?

A
  1. Neurofilament accumulation
  2. Transgenic mice that overexpress neurofilament proteins show motor neuron degeneration
  3. Variant alleles of the neurofilament heavy-subunit gene have been found in ALS patients
56
Q

What does mutant SOD1 on fast axonal transport (FAT) REVEAL?

A

mutant SOD1 reduces transport of membrane-bound organelles in both anterograde and retrograde directions

57
Q

Where is mitochondrial transport selectively reduced?

A

Anterograde direction

58
Q

What does a mutation in dynein rescue?

A

Axonal transport defects and extends the life span of ALS mice

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