Neurodegenerative Disorders

Question 1

Neurodegenerative Disease

Answer 1

disorders w/ progressive loss of neurons which have shared function

Question 2

Etiopathogenesis of Neurodegenerative disease

Answer 2

• Not understood
• MOST HAVE ACCUMULATION OF PROTEIN AGGREGATES

Question 3

CFs of Alzheimer

Answer 3

• Memory impairment (Short-term –> long-term)
• Altered mood & behavior
• Impaired cognition
• Aphasia & disorientation

NB: motor & sensory system usually intact

Question 4

Diagnosis & Cause of death in Alzheimer

Answer 4

• MSE
• Histo (autopsy)

COD= Intercurrent pneumonia or other infection

Question 5

Etiopathogenesis of Alzheimer

Answer 5

Accumulation of AB & Tau proteins as plaques & tangles –> Neuronal death & inflammation

Question 6

Formation of plaques in Alzheimer Disease

Answer 6

Amyloid precursor protein (APP) mutation –> AB monomer –> AB oligomers –> AB peptide aggregation –> Neuronal damage

• Extracellular
• Gene on Chr 21 (down syndrome association)
• APP broken down into fragments by Secretase

Question 7

Formation of Neurofibrillary tangles in Alzheimer

Answer 7

Aggregation of Tau proteins (microtubule-associated proteins) in axons

• AB oligomers activates kinases –> Hyper-phosphorylate tau –> Loses ability to bind microtubules –> Aggregation
• INTRACELLULAR then goes EXTRACELLULAR after neuronal death

Question 8

Types o Alzheimer Disease

Answer 8

Inherited (20%)
1. Early onset
- APP on Chr 21 –> AB amyloid formation
- Presenilin gene on Chr 1 & 14 and y-secretase
2. Late onset
- Tau protein
- Apo E on Chr 19 – 3 allelic form (e2, e3 & e4 )
Homozygosity of e4 is worst
Sporadic (80%)

Question 9

Gross morphology of brain w/ Alzheimer

Answer 9

• Atrophy - frontal, temporal & parietal lobes
• Cerebral sulci widening
• Ventricular enlargement - Hydrocephalus ex vacuo

Question 10

Microscopic changes in brain w/ Alzheimer Disease

Answer 10

• Neuronal loss in cerebral cortex
• Gliosis - Astrocyte proliferation & hypertrophy
• Neurofibrillary tangles & neuritic plaques

Question 11

Frontotemporal Lobar Degeneration (FTLD)

Answer 11

disorder affecting the frontal and/or temporal lobes

Question 12

CFs of FTLD

Answer 12

• Progressive behavioral changes OR
• Language problems
• Memory disturbance (late - differentiate from Alzheimer)

Question 13

Epidemiology of FTLD

Answer 13

Younger ages (differentiate from Alzheimer)

Question 14

Etiopathogenesis of FTLD

Answer 14

• FTLD-tau (Tau accumulation - Also in Alzheimer)
• FTLD-TDP

Question 15

Gross morphology of FTLD

Answer 15

• Temporal cortex atrophy

NB: Relative frontal cortex preservation

Question 16

Microscopic changes in FTLD

Answer 16

Cytoplasmic inclusion w/ TDP43 proteins

Question 17

Parkinson Disease

Answer 17

NDD w/ hypokinetic movement due to loss of dopaminergic neurons in Substantia nigra

Question 18

Etiopathogenesis of Parkinson

Answer 18

• Substantia Nigra - Protein accumulation, mitochondrial abnormalities & dopaminergic neuronal loss
• Mutation in a-synuclein gene (autosomal dominant)

Question 19

CFs of Parkinson

Answer 19

• Tremor (asymmetric pill rolling)
• Rigidity (cogwheel)
• Bradykinesia/ Akinesia (shuffling gait)
• Postural instability
• Masked facies, hypokinetic dysarthria, micrographia & sleep disorder
• Dementia (fluctuates) & hallucination (LATE)

Question 20

Gross morphology of Parkinson

Answer 20

• Substania nigra - Pallor & atrophy

Question 21

Microscopic changes in parkinson

Answer 21

• Loss of pigmented neurons w/ gliosis
• Lewy bodies (cytoplasmic eosinophilic inclusions - filaments composed of a-synuclein)

Question 22

Progression & Cause of death in Parkinson

Answer 22

progress over 10-15 year

COD = aspirational pneumonia OR trauma from falls

Question 23

Lewy body Dementia

Answer 23

When dementia & hallucinations occurs within 1 year of motor symptoms in Parkinson

Question 24

Amyotrophic Lateral Sclerosis

Answer 24

NDD due to death of LMN in the spinal cord & brain stem AND UMN in the motor cortex

Question 25

Pathogenesis of ALS

Answer 25

- Uncertain - Abnormal RNA and/or Protein processing Mutations - Chr 9 Hexanucleotide repeat - Superoxide Dismutase gene

Question 26

Epidemiology of ALS

Answer 26

- M>F - 50 years - Life expectancy = 2-5 years after onset - Sporadic (mostly) or Familial (10%) - AD inheritance)

Question 27

CFs of ALS

Answer 27

- Asymmetric distal extremity weakness Loss of LMN --> Denervation of muscles --> Atrophy - weakness & fasciculations Loss of UMN - Paresis, spasticity, hyperreflexia, Babinski sign & Degeneration of corticospinal tract in lateral portion of spinal cord Cognition may be impaired. But intellect, sensation, sphincter control & eye movement are SPARED.

Question 28

Cause of Death in ALS

Answer 28

Recurrent Pulmonary Infections

Question 29

Gross morphology of ALS

Answer 29

- Thinning of Anterior roots of spinal cord - Atrophy of Precentral motor cortex

Question 30

Microscopic changes in ALS

Answer 30

- Dec # of neurons in anterior horn in spinal cord - Neurogenic atrophy in skeletal muscles - Reactive gliosis - Loss of anterior root myelinated fibers

Question 31

Huntington Chorea/Disease

Answer 31

Movement disorder associated with degeneration of Striatum (Caudate & Putamen)

Question 32

CFs of Huntington

Answer 32

MOTOR - Chorea - Athetosis - Dystonia - Impaired gait, posture & balance - Difficulty in speech & eye movements COGNITION & PHYCHIATRY - Forgetfulness (early) - Difficulty organizing tasks & lack of impulse control - Dementia - Increase risk of suicide

Question 33

Etiopathogenesis of Huntington

Answer 33

- CAG repeats ( 39-250 repeats) - Gain of function mutation of Huntingtin gene on Chr 4 -Mutant protein + ubiquitination + proteolysis --> Intranuclear fragments --> Disrupts protein degradation & mitochondrial function & sequester transcription factors - ANTICIPATION- Paternal transmission results in earlier onset in next generation

Question 34

Gross morphology of Huntington

Answer 34

- Atrophy of Caudate nucleus & Putamen - Dilated lateral & third ventricles

Question 35

Microscopic changes in Huntington

Answer 35

- Neuronal loss w/ gliosis - Intranuclear inclusions w/ ubiquitinated Huntington protein

Question 36

Progression & Cause of death in Huntington

Answer 36

- Progressive - Death after about 15 years