Kraft Block 5

Question 1

What are the gross brain features in HD?

Answer 1

• Small brain
• Atrophic striatum
  
  • Caudate nucleus is very small/flat
• Atrophic frontal lobe
• Dilated lateral/3rd ventricles

Question 2

What is the gross brain grading in HD based on?

Answer 2

• Level of atrophy can be used to determine grade
  
  • 0-1: no gross atrophy
  • 2: some atrophy but caudate still remains convex (bulges into ventricle)
  • 3: caudate is flat
  • 4: caudate becomes concave

Question 3

What are the microscopic features of HD?

Answer 3

• Severe loss of striatal neurons, esp. medium spiny neurons
  
  • Degree of degeneration directly related to severity of clinical Sx
• Extensive fibrillary gliosis (Astrocyte proliferation)
• Huntingtin protein aggregates in neurons
  
  • Gene for this protein is abnormal –> expansion of trinucleotide sequence CAG
  • form a basket-like structure of long proteins

                                                à catches other proteins

Question 4

What cell types are present/absent in microscopic examination of the HD brain?

Answer 4

• Cell types
  
  • Neurons: none present in HD
  • Oligodendrocytes: lots
    
    • compact chromatin with halo around
  • Astrocytes: lots
    
    • dark circle with non-compact chromatin, no halo

Question 5

What does the presence of ubiquitin mean?

Answer 5

• Ubiquitin stain = surrogate marker
  
  • misfolded protein is not removed like it should be
  • stays attached to ubiquitin

Question 6

What is the pathogenesis of HD according to Dr. Krafts?

Answer 6

• Loss of neurons in BG
• Spiny striatal neurons dampen motor activity
  
  • Taking off the brakes
  • Lose these –> get increased motor output –> Choreathetosis
• Cognitive changes related to neuronal loss from cortex
  
  • Prefrontal loop in BG
  • Loop involved in personality and behavior

Question 7

What are the common causes of global cerebral ischemia?

Answer 7

• Hypotension
  
  • diminish blood flow to the entire brain
• “Watershed” infarcts
  
  • areas at the border of two different blood supplies
• laminar necrosis
  
  • “band like” area of hypoxic injury in one area
• diffuse necrosis (liquifactive)
  
  • global damage to entire brain
  • “respirator brain” does not get enough blood supply to brain on respirator
  • really bad hypotensive episode

Question 8

In terms of global cerebral ischemia, what are the potential consequences to the brain?

Answer 8

• Thinned cortex
• Loss of brain mass (shrinks)
• Liquifactive necrosis
  
  • tissue becomes very soft and falls apart

Question 9

What is the typical cause of of hemorrhagic (red) infarcts?

Answer 9

• Usually due to emboli + reperfusion
  
  • emboli composed of blood clot (heart/carotid) or of marrow/fat/tumor
  • something was plugging vessel then dislodged and blood poured out of it
• Usually in MCA at branch points

Question 10

What is the morphologic appearance of hemorrhagic (red) infarcts?

Answer 10

• Gross
  
  • Punctate hemorrhages or big hematomas
  • Eventual resolution and cavitation
• Microscopic (extravasated blood)
  
  • red neurons
  • edema
  • swollen astrocytes
  • lots of neutrophils
  • less neutrophils, then more macrophages
  • gliosis begins
  • even more macrophages
  • dense gliosis & new capillaries

Question 11

What is the typical cause of ischemic (pale) infarcts?

Answer 11

• Usually due to thrombi
  
  • often arise from atherosclerotic plaques
• Usually at carotid bifurcation, MCA origin, or ends of basilar artery

Question 12

What is the morphologic appearance of ischemic (pale) infarcts?

Answer 12

• Gross appearance
  
  • First two days: pale, edema, wet
  • 2-10 days: gelatinous, outlines of infarct visible
  • 10-21 days: liquefaction and cavitation
• Microscopic
  
  • red neurons
  • edema
  • swollen astrocytes
  • lots of neutrophils
  • less neutrophils, then more macrophages
  • gliosis begins
  • even more macrophages
  • dense gliosis & new capillaries

Question 13

What brain findings may be seen in patients with hypertension?

Answer 13

• Lacunar infarcts
  
  • deep vessels supplying basal ganglia, deep white matter, and brain stem
  • develop arteriolar sclerosis –> can become occluded
  • vessels become thicker due to increased tension
  • tissue loss with macrophages, gliosis
• Slit hemorrhages
  
  • hypertension causes rupture of little penetrating vessels
  • over time, hemorrhages resorb leaving a brownish, slit-like cavity

Question 14

What are the clinical features of intraparenchymal hemorrhage?

Answer 14

• peak age = 60, high mortality
• usually due to rupture of a small intraparenchymal vessel
• can be “ganglionic” or “lobar”
• Most common cause = hypertension

Question 15

What are the predisposing causes of intraparenchymal hemorrhage?

Answer 15

• Hypertension causes:
  
  • accelerated atherosclerosis
  • hyaline arteriolosclerosis
  • even frank necrosis
  • vessel walls are weaker
  • sometime see tiny aneurysms
    
    • Charcot-Bouchard microaneurysms = outpouching of vessel wall

Question 16

What are the clinical features of subarachnoid hemorrhage?

Answer 16

• Severe headache (“worst ever”)
• Loss of consciousness in minutes
• Death in 25-50%
• If survive, regain consciousness
• At risk for vasospastic injury, communicating hydrocephalus

Question 17

What are the predisposing causes of subarachnoid hemorrhage?

Answer 17

• Berry aneurysm
  
  • thin walled sac with fragmented media
  • unknown etiology, most sporadic
  • ​Smoking
  • hypertension present in half of patients
  • grow slowly (when >1cm 50% risk of bleeding per year)
  • most common at arterial branch points
  • high mortality when ruptured

Question 18

What are the clinical features of Alzheimer disease?

Answer 18

• Main symptom = dementia
  
  • early on forgetfulness, mood/behavior changes
  • later disorientation, memory loss, aphasia, loss of motor skills
• Prognosis = 3-20 years
  
  • in 5-10 years patient will be profoundly disabled, mute, immobile
• Death usually from infection (pneumonia)

Question 19

What are the morphological findings in Alzheimer disease?

Answer 19

• Major degenerative disease of the cortex
• Gross: atrophy
• Microscopic: plaques and tangles
  
  • neuritic plaques: Aß peptides forming amyloid plaques around neuron
  • neurofibrillary tangles: bundles of filaments IN neuron cytoplasm composed of tau, MAP2, & ubiquitin
  • neuronal loss and gliosis
  • cerebral amyloid angiopathy (amyloid in vessels)

Question 20

What is the pathogenesis of Alzheimer disease?

Answer 20

• Main abnormality = deposition and accumulation of Aß peptides
  
  • Aß comes from abnormal processing of amyloid precursor protein
  • Aß accumulates, forms amyloid aggregates
  • Aggregates are neurotoxic and pro-inflammatory
  • Tau accumulation seems to be a secondary phenomenon
    
    • caused by abnormal Aß

Question 21

What are the clinical features of Pick disease?

Answer 21

• “Frontotemporal lobar degeneration/dementia” = FTLD
  
  • fairly common cause of early-onset dementia (younger patients <60 yoa)
• Personality and language changes preced memory loss
  
  • First: frontal lobe signs (personality changes) and temporal lobe signs (language disturbances)
  • Later: dementia

Question 22

What are the morphologic findings in Pick disease?

Answer 22

• Severe atrophy of frontal and temporal lobes
  
  • can cause ex-vacuo hydrocephalus
• Neuronal loss
• Pick bodies containing tau protein

Question 23

What are the clinical features of Parkinson disease?

Answer 23

• Main symptoms: tremor, rigidity, bradykinesia
• Parkinsonism
  
  • diminished facial expression
  • stooped posture
  • slowness of voluntary movement
  • festinating gait (slow –> fast)
  • rigidity
  • “pill-rolling” tremor
• Some patients have dementia
• Autonomic and cognitive dysfunction common
• Prognosis: slightly shortened life expectancy

Question 24

What are the morphologic findings in Parkinson disease?

Answer 24

• Degeneration of neurons in substantia nigra
• Gross: atrophy of substantia nigra
  
  • pallor of substantia nigra due to loss of pigmented neurons
• Microscopic: Lewy bodies

Question 25

What is the pathogenesis of Parkinson disease?

Answer 25

• 5 genes encoding totally different products known to be associated with PD
• No unifying mechanism known
• Maybe alpha-synuclein, maybe something else
• Whatever the cause, the problem is degeneration of dopaminergic neurons

Question 26

What are the clinical features of amyotrophic lateral sclerosis (ALS)?

Answer 26

• Rapidly progressive weakness, spasticity, dysphagia
  
  • Early: asymmetric hand weakness, arm/leg spasticity, twitching, slurred speech
  • Later: atrophy, fasciculations, creeping paralysis
  • Eventually respiratory muscles involved
• Sensory and cognitive function are unaffected
• Death within 2-3 years due to respiratory compromise (or infection)

Question 27

What are the morphologic findings in amyotrophic lateral sclerosis (ALS)?

Answer 27

• Thin anterior roots of spinal cord
• Degeneration of corticospinal tracts
• Decrease in anterior horn neurons
• Skeletal muscles atrophied

Question 28

What is the pathogenesis of ALS?

Answer 28

• Cause of motor neuron degeneration not well understood
• SOD is mutated in some inherited cases - but lack of detoxification doesn’t seem to be the cause
• Bottom line: neuronal degeneration, often with toxic protein accumulation