Degenerative Diseases Part 1 Flashcards
Overview of degenerative diseases:
What are they?
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
Overview of degenerative diseases:
What are inclusions seen in Huntington’s, Alzheimer’s, and Parkinson’s?
- Huntington’s: Polyglutamine repeats; mutated protein
- Alzheimer’s: Beta-amyloid peptide derived from larger precursor protein
- Parkinson’s: Alpha-synuclein
What is Alzheimer’s?
Insidious impairment of higher intellectual fxn w alterations in mood & behavior
Initial sx of Alz?
More progression?
Late sx?
Initial: Forgetfulness & other memory disturbances
Later: Language deficits, loss of math skills, loss of learned motor skills
Late: Incontinent, mute, unable to walk
What parts of the brain atrophy in Alz?
Global atrophy
- Cortical atrophy w widening of sulci
- Frontal, temporal (hippo, entorhinal cortex, amygdala), parietal lobes
What are 2 pathological hallmarks of Alz? What are they comprised of?
- Amyloid plaques: Deposits of aggregated beta-amyloid peptides in the neurophil; outside neurons
- Neurofibrillary tangles: Aggregates of microtubule binding protein tau; inside neurons
What is good correlation for degree of dementia in Alz?
Number of neurofibrillary tangles
- HOWEVER tangles are not specific to Alz but plaques are
What is the critical initiating event for development of Alz?
Beta-amyloid generation
What genetic locus (and on which chromosome) has high risk of developing Alz?
Apolipoprotein E (ApoE) on chromosome 19
What are the two types of plaques in Alz?
- Neuritic plaques
- Diffuse plaques
What is a neuritic plaque in Alz?
Where do you see them?
How do you stain for them?
Focal, spherical collections of dilated tortuous neuritis processes around amyloid core
Seen in hippo, amygdala, neocortex
Amyloid core stains with congo red stain
What are diffuse plaques in Alz?
Where do you see them?
No amyloid core
Seen in superficial cortex, basal ganglia, cerebellar cortex
What is the correlation between Downs syndrome and Alz?
Often times people with Downs have early-onset Alz
- Gene that encodes APP is in chromosome 21, people with Downs have extra chromosome 21
What are neurofibrillary tangles? What stain can you use?
What is tau?
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
Other than plaques and tangles, what are two things you see on histo with Alz?
- 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
What is a disorder that “invariably accompanies” Alz?
Cerebral amyloid angiopathy
What are frontotemporal lobar degenerations (FTLDS)?
Heterogenous group of disorders w focal degeneration of frontal and/or temporal lobes
What are 2 inclusions that can be seen in frontotemporal lobar degenerations?
- Tau inclusions (FTLD-tau): Includes Pick disease
- TDP-43 inclusions (FTLD-TDP)
What is Pick disease (FTLD-TAU)
Rare, distinct, progressive dementia that has early onset behavioral changes e alterations in personality (frontal lobe sign) & language disturbances (temporal lobe sign)
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?
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
What are some sx of progressive supranuclear palsy? (FTLD-TAU)
- 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
Typical prognosis for progressive supranuclear palsy?
What is this also considered?
Fatal w/i 5-7 years of onset
“Atypical parkinsonian syndrome” or “Parkinsonian plus syndrome”
Where in the brain does progressive supranuclear palsy affect?
Widespread neuronal loss in:
- Globus pallidus
- Subthalamic nucleus
- Substantia nigra
- Colliculi
- Periaqueductal grey matter
- Dentate nucleus of cerebellum
What do you see on histo w progressive supranuclear palsy?
- Globose neurofibrillary tangles
- 4R tau straight filaments
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?
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
What are sx of Parkinsonism?
- Diminished facial expressions (“masked facies”)
- Stooped posture
- Slowness (bradykinesia) of voluntary movement
- Festinating gait
- Rigidity
- “Pill-rolling” tremor
What are some diseases that exhibit “parkinsonism”? (6)
- Parkinson Disease
- Multiple System Atrophy
- Postencephalitic Parkinsonism
- Progressive supranuclear palsy
- Corticobasilar degeneration (CBD)
- MPTP (contaminant in synthetic heroin that destroys neurons of substantia nigra)
What causes Parkinson Disease?
Protein accumulation & aggregation, mitochondrial abnormalities, & neural loss in substantia nigra. Loss of dopaminergic neurons from substantia nigra
What does loss of dopaminergic neurons in substantia nigra cause in Parkinsons?
What are the L-Dopa-responsive signs?
Loss of dopa neurons: Hypokinetic movement disorders
L-Dopa signs: Tremor, rigidity, bradykinesia
Tx of Parkinsons?
Carbidopa admin to inhibit periph metabolism of levodopa (L-Dopa). This allows greater proportion of peripheral levodopa to cross BBB for CNS effect
What are some mutated genes in Parkinsons?
- SNCA: Encodes for alpha-synuclein on chromosome 4q21
- DJ-1, PINK1, PARKIN: Mitochondrial dysfxn
- LRRK2
- Heterozygous mutations in glucocerebrosidase
What is the gross morphology of Parkinsons?
What can you see on histo and what is a key inclusion?
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
What is dementia w lewy bodies? What do we see grossly in the brain?
Parkinson Disease w dementia
- Hallucinations and prominent frontal signs
- Depigmentation of substantia nigra & locus ceruleus w relative preservation of cortex, hippo, amygdala
What are 3 major atypical parkinsonian syndromes (aka parkinson-plus syndromes)?
- Progressive supranuclear palsy
- Corticobasal degeneration
- Multisystem atrophy
Note: Minimally responsive to L-Dopa tx
What is corticobasal degeneration?
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
CBD and PSP share many clinical and pathologic features. What are distinguishing features?
- 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
What are 3 buzz word phrases in relation to tau and CBD?
- Tufted astrocytes (tau in astrocytes)
- Coiled bodies (tau in oligodendrocytes)
- Astrocytic plaques (cluster of tau-positive processes around astrocytes)
What is the most specific pathologic finding of CBD?
Presence of tau-positive threads in grey and white matter
What is multiple system atrophy?
Sporadic disorder that affects a number of different systems in the brain
- Alpha-synuclein cytoplasmic inclusions in oligodendrocytes
What 3 distinct systems are involved in multiple system atrophy?
- Striatonigral circuit: Parkinsonism
- Olivopontocerebellar circuit: Ataxia
- ANS: Autonomic dysfxn
