Neurodegenerative Disorders Flashcards
Neurodegenerative Disease
disorders w/ progressive loss of neurons which have shared function
Etiopathogenesis of Neurodegenerative disease
- Not understood
- MOST HAVE ACCUMULATION OF PROTEIN AGGREGATES
CFs of Alzheimer
- Memory impairment (Short-term –> long-term)
- Altered mood & behavior
- Impaired cognition
- Aphasia & disorientation
NB: motor & sensory system usually intact
Diagnosis & Cause of death in Alzheimer
- MSE
- Histo (autopsy)
COD= Intercurrent pneumonia or other infection
Etiopathogenesis of Alzheimer
Accumulation of AB & Tau proteins as plaques & tangles –> Neuronal death & inflammation
Formation of plaques in Alzheimer Disease
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
Formation of Neurofibrillary tangles in Alzheimer
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
Types o Alzheimer Disease
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%)
Gross morphology of brain w/ Alzheimer
- Atrophy - frontal, temporal & parietal lobes
- Cerebral sulci widening
- Ventricular enlargement - Hydrocephalus ex vacuo
Microscopic changes in brain w/ Alzheimer Disease
- Neuronal loss in cerebral cortex
- Gliosis - Astrocyte proliferation & hypertrophy
- Neurofibrillary tangles & neuritic plaques
Frontotemporal Lobar Degeneration (FTLD)
disorder affecting the frontal and/or temporal lobes
CFs of FTLD
- Progressive behavioral changes OR
- Language problems
- Memory disturbance (late - differentiate from Alzheimer)
Epidemiology of FTLD
Younger ages (differentiate from Alzheimer)
Etiopathogenesis of FTLD
- FTLD-tau (Tau accumulation - Also in Alzheimer)
- FTLD-TDP
Gross morphology of FTLD
- Temporal cortex atrophy
NB: Relative frontal cortex preservation
Microscopic changes in FTLD
Cytoplasmic inclusion w/ TDP43 proteins
Parkinson Disease
NDD w/ hypokinetic movement due to loss of dopaminergic neurons in Substantia nigra
Etiopathogenesis of Parkinson
- Substantia Nigra - Protein accumulation, mitochondrial abnormalities & dopaminergic neuronal loss
- Mutation in a-synuclein gene (autosomal dominant)
CFs of Parkinson
- Tremor (asymmetric pill rolling)
- Rigidity (cogwheel)
- Bradykinesia/ Akinesia (shuffling gait)
- Postural instability
- Masked facies, hypokinetic dysarthria, micrographia & sleep disorder
- Dementia (fluctuates) & hallucination (LATE)
Gross morphology of Parkinson
- Substania nigra - Pallor & atrophy
Microscopic changes in parkinson
- Loss of pigmented neurons w/ gliosis
- Lewy bodies (cytoplasmic eosinophilic inclusions - filaments composed of a-synuclein)
Progression & Cause of death in Parkinson
progress over 10-15 year
COD = aspirational pneumonia OR trauma from falls
Lewy body Dementia
When dementia & hallucinations occurs within 1 year of motor symptoms in Parkinson
Amyotrophic Lateral Sclerosis
NDD due to death of LMN in the spinal cord & brain stem AND UMN in the motor cortex
Pathogenesis of ALS
- Uncertain
- Abnormal RNA and/or Protein processing
Mutations
- Chr 9 Hexanucleotide repeat
- Superoxide Dismutase gene
Epidemiology of ALS
- M>F
- 50 years
- Life expectancy = 2-5 years after onset
- Sporadic (mostly) or Familial (10%) - AD inheritance)
CFs of ALS
- 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.
Cause of Death in ALS
Recurrent Pulmonary Infections
Gross morphology of ALS
- Thinning of Anterior roots of spinal cord
- Atrophy of Precentral motor cortex
Microscopic changes in ALS
- Dec # of neurons in anterior horn in spinal cord
- Neurogenic atrophy in skeletal muscles
- Reactive gliosis
- Loss of anterior root myelinated fibers
Huntington Chorea/Disease
Movement disorder associated with degeneration of Striatum (Caudate & Putamen)
CFs of Huntington
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
Etiopathogenesis of Huntington
- 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
Gross morphology of Huntington
- Atrophy of Caudate nucleus & Putamen
- Dilated lateral & third ventricles
Microscopic changes in Huntington
- Neuronal loss w/ gliosis
- Intranuclear inclusions w/ ubiquitinated Huntington protein
Progression & Cause of death in Huntington
- Progressive
- Death after about 15 years
