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NMSP Exam 1 > Degenerative Diseases Part 1 > Flashcards

Degenerative Diseases Part 1 Flashcards

1
Q

Overview of degenerative diseases:

What are they?

A

Progressive loss of neurons a/w secondary changes in white matter tracts

  • Diseases of grey matter
  • Presence of protein aggregates that are resistant to degradation thru ubiquitin-proteasome system
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2
Q

Overview of degenerative diseases:

What are inclusions seen in Huntington’s, Alzheimer’s, and Parkinson’s?

A
  • Huntington’s: Polyglutamine repeats; mutated protein
  • Alzheimer’s: Beta-amyloid peptide derived from larger precursor protein
  • Parkinson’s: Alpha-synuclein
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3
Q

What is Alzheimer’s?

A

Insidious impairment of higher intellectual fxn w alterations in mood & behavior

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4
Q

Initial sx of Alz?

More progression?

Late sx?

A

Initial: Forgetfulness & other memory disturbances

Later: Language deficits, loss of math skills, loss of learned motor skills

Late: Incontinent, mute, unable to walk

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5
Q

What parts of the brain atrophy in Alz?

A

Global atrophy

  • Cortical atrophy w widening of sulci
  • Frontal, temporal (hippo, entorhinal cortex, amygdala), parietal lobes
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6
Q

What are 2 pathological hallmarks of Alz? What are they comprised of?

A
  • Amyloid plaques: Deposits of aggregated beta-amyloid peptides in the neurophil; outside neurons
  • Neurofibrillary tangles: Aggregates of microtubule binding protein tau; inside neurons
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7
Q

What is good correlation for degree of dementia in Alz?

A

Number of neurofibrillary tangles

- HOWEVER tangles are not specific to Alz but plaques are

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8
Q

What is the critical initiating event for development of Alz?

A

Beta-amyloid generation

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9
Q

What genetic locus (and on which chromosome) has high risk of developing Alz?

A

Apolipoprotein E (ApoE) on chromosome 19

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10
Q

What are the two types of plaques in Alz?

A
  • Neuritic plaques

- Diffuse plaques

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11
Q

What is a neuritic plaque in Alz?

Where do you see them?

How do you stain for them?

A

Focal, spherical collections of dilated tortuous neuritis processes around amyloid core

Seen in hippo, amygdala, neocortex

Amyloid core stains with congo red stain

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12
Q

What are diffuse plaques in Alz?

Where do you see them?

A

No amyloid core

Seen in superficial cortex, basal ganglia, cerebellar cortex

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13
Q

What is the correlation between Downs syndrome and Alz?

A

Often times people with Downs have early-onset Alz

- Gene that encodes APP is in chromosome 21, people with Downs have extra chromosome 21

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14
Q

What are neurofibrillary tangles? What stain can you use?

What is tau?

A

Bundles of filaments in cytoplasm of neurons that displace or encircle nucleus; can use Bielschowsky stain (silver stain)

Tau is an abnormally hyperphosphorylated axonal microtubule- associated protein that enhances microtubule assembly –> tangles
- MAP2 & ubiquitin

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15
Q

Other than plaques and tangles, what are two things you see on histo with Alz?

A
  • Granulovascular degeneration: Small clear intraneuronal cytoplasmic vacuoles which contain argyrophilic granules; normal finding w age but abundant in Alz w/i hippo & olfactory bulb
  • Hirano bodies: Elongated glassy eosinophilic bodies; actin is major component
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16
Q

What is a disorder that “invariably accompanies” Alz?

A

Cerebral amyloid angiopathy

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17
Q

What are frontotemporal lobar degenerations (FTLDS)?

A

Heterogenous group of disorders w focal degeneration of frontal and/or temporal lobes

18
Q

What are 2 inclusions that can be seen in frontotemporal lobar degenerations?

A
  • Tau inclusions (FTLD-tau): Includes Pick disease

- TDP-43 inclusions (FTLD-TDP)

19
Q

What is Pick disease (FTLD-TAU)

A

Rare, distinct, progressive dementia that has early onset behavioral changes e alterations in personality (frontal lobe sign) & language disturbances (temporal lobe sign)

20
Q

What part of the brain is affected by Pick disease? What are some characteristics of the brain? What are 2 specific things you’ll see on histo?

A

Asymmetric atrophy or the frontal and temporal lobes w sparing of the posterior 2/3 of the superior temporal gyrus (clear demarcation of affected brain)

  • “Knife-edge” thin gyri
  • Pick cells: Swollen cells
  • Pick bodies: Cytoplasmic filamentous inclusions that are weakly basophilic & stain strongly w silver
21
Q

What are some sx of progressive supranuclear palsy? (FTLD-TAU)

A
  • Progressive truncal rigidity w disequilibrium (freq falls)
  • Difficulty w voluntary eye movements including vertical gaze palsy progressing to difficulty w all eye movements
  • Nuchal dystonia
  • Pseudobulbar palsy & abnormal speech
  • Mild progressive dementia
22
Q

Typical prognosis for progressive supranuclear palsy?

What is this also considered?

A

Fatal w/i 5-7 years of onset

“Atypical parkinsonian syndrome” or “Parkinsonian plus syndrome”

23
Q

Where in the brain does progressive supranuclear palsy affect?

A

Widespread neuronal loss in:

  • Globus pallidus
  • Subthalamic nucleus
  • Substantia nigra
  • Colliculi
  • Periaqueductal grey matter
  • Dentate nucleus of cerebellum
24
Q

What do you see on histo w progressive supranuclear palsy?

A
  • Globose neurofibrillary tangles

- 4R tau straight filaments

25
Q

What do degenerative diseases of the basal ganglia and brainstem affect?

What is the pathway w/i the the basal ganglia and what role does it play?

A

These areas are a/w movement disorders
- Rigidity, abnormal posturing, chorea

The basal ganglia, esp the nigrostridal pathway, plays an impt role in regulation of synaptic pathways that modulate feedback from the thalamus to motor cortex

26
Q

What are sx of Parkinsonism?

A
  • Diminished facial expressions (“masked facies”)
  • Stooped posture
  • Slowness (bradykinesia) of voluntary movement
  • Festinating gait
  • Rigidity
  • “Pill-rolling” tremor
27
Q

What are some diseases that exhibit “parkinsonism”? (6)

A
  • Parkinson Disease
  • Multiple System Atrophy
  • Postencephalitic Parkinsonism
  • Progressive supranuclear palsy
  • Corticobasilar degeneration (CBD)
  • MPTP (contaminant in synthetic heroin that destroys neurons of substantia nigra)
28
Q

What causes Parkinson Disease?

A

Protein accumulation & aggregation, mitochondrial abnormalities, & neural loss in substantia nigra. Loss of dopaminergic neurons from substantia nigra

29
Q

What does loss of dopaminergic neurons in substantia nigra cause in Parkinsons?

What are the L-Dopa-responsive signs?

A

Loss of dopa neurons: Hypokinetic movement disorders

L-Dopa signs: Tremor, rigidity, bradykinesia

30
Q

Tx of Parkinsons?

A

Carbidopa admin to inhibit periph metabolism of levodopa (L-Dopa). This allows greater proportion of peripheral levodopa to cross BBB for CNS effect

31
Q

What are some mutated genes in Parkinsons?

A
  • SNCA: Encodes for alpha-synuclein on chromosome 4q21
  • DJ-1, PINK1, PARKIN: Mitochondrial dysfxn
  • LRRK2
  • Heterozygous mutations in glucocerebrosidase
32
Q

What is the gross morphology of Parkinsons?

What can you see on histo and what is a key inclusion?

A

Pallor of substantia nigra and locus ceruleus

Lewy bodies: Cytoplasmic, eosinophilic, round-elongated inclusions that have a dense core surrounded by a pale halo
- Alpha-synuclein fine filaments are packed at the core

33
Q

What is dementia w lewy bodies? What do we see grossly in the brain?

A

Parkinson Disease w dementia

  • Hallucinations and prominent frontal signs
  • Depigmentation of substantia nigra & locus ceruleus w relative preservation of cortex, hippo, amygdala
34
Q

What are 3 major atypical parkinsonian syndromes (aka parkinson-plus syndromes)?

A
  • Progressive supranuclear palsy
  • Corticobasal degeneration
  • Multisystem atrophy

Note: Minimally responsive to L-Dopa tx

35
Q

What is corticobasal degeneration?

A

CBD is a progressive tauopathy w extrapyramidal rigidity, asymmetric motor disturbance (jerking), & impaired higher cortical fxn (apraxia)
- Cognitive decline may occur but later in the illness

36
Q

CBD and PSP share many clinical and pathologic features. What are distinguishing features?

A
  • In PSP there is a greater burden of tau-containing lesions in the brainstem & deep grey matter
  • CBD has greater burden of tau-containing lesions in the cerebral cortex
37
Q

What are 3 buzz word phrases in relation to tau and CBD?

A
  • Tufted astrocytes (tau in astrocytes)
  • Coiled bodies (tau in oligodendrocytes)
  • Astrocytic plaques (cluster of tau-positive processes around astrocytes)
38
Q

What is the most specific pathologic finding of CBD?

A

Presence of tau-positive threads in grey and white matter

39
Q

What is multiple system atrophy?

A

Sporadic disorder that affects a number of different systems in the brain
- Alpha-synuclein cytoplasmic inclusions in oligodendrocytes

40
Q

What 3 distinct systems are involved in multiple system atrophy?

A
  • Striatonigral circuit: Parkinsonism
  • Olivopontocerebellar circuit: Ataxia
  • ANS: Autonomic dysfxn

NMSP Exam 1 (9 decks)

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