P- Neurodegenerative Disorders Flashcards
__________ is the most debilitating neurologic disease among young adults and is due to autoimmune mechanism.
____________ occur primarily in children and are the result of inborn errors of metabolism.
MS is the most debilitating neurologic disease in young people.
Leukodystrophies occur in children as the result of inborn errors of metabolism of enzymes affecting the production and maintenance of myelin
What is selective vulnerability?
What 3 things determine the CNS components involved?
The brain is the most inhomogenous organ in the body. Even if the whole CNS is exposed to an insult, only specific regions, groups of cells or cell components will be damaged.
- location in nervous system
- shared biochemical properties [same neurotransmitter]
- undetermined factors
What CNS components are at highest risk for brain contusions? What is the basis?
The orbital and temporal regions are at highest risk for contusion because of the irregularities in the inner skull surface at these locations
What CNS components are at highest risk for ischemia? What is the basis?
- CA1 of hippocampus
- Purkinje cells of cerebellum
Because they have the highest concentration in glutamate receptors which can lead to excitotoxicity and cell death
[ischemia= low flow= build up of glutamate = excitotoxicity = apoptosis of neurons]
What CNS components are at highest risk for CO intoxication? What is the basis?
- globus pallidus
- substantia nigra
highest concentration of iron-containing substances and thus highest affinity for CO
What CNS component is at highest risk for methanol intoxication? Basis?
Putamen- unknown reasons
What CNS component is at highest risk for damage by chronic ethanol use?
anterior cerebellar vermis- unknown reason
What CNS component is at highest risk for damage by neurodegenerative disorders?
- Transmitter specific groups of neurons
2. glia
What 2 disorders disrupt myelin?
What is the basis of each?
- MS - autoimmune attack on myelin-associated antigens
2. Leukodystophies- deficiency in enzyme that produces or maintains myelin [inborn error of metabolism]
What is the major risk factor for developing AD?
Advancing age
1% of 60 year olds to 50% of 80year olds
How does AD manifest clinically?
What area of the brain is the deterioration of the brain localized to?
How long is the course of the disease?
What causes death in most AD patients?
It manifests as dementia:
- amnesia and atleast one of the following:
- apraxia, aphasia, agnosia, decreased exec func
There is generalized, global deterioration of the cerebral cortex [outer gray, neuron rich matter]
Onset is insidious, and the course of the disease can be a decade or more.
Death is usually caused by secondary illness that complicates the debilitated state [pneumonia, UTI, sepsis, trauma]
What are the 2 ways atrophy of the brain can manifest in patients with Alzheimer’s?
- cerebral cortical atrophy [narrowed, gyri, wide sulci]
2. hydrocephalus ex vacuo [dilated ventricles due to loss of brain parenchyma]
What are the chief neuropathologic features of AD?
- neurofibrillary tangles - in cytoplasm of neuron
2. senile plaques - in dendrites/axons
What is the pathophysiology behind a neurofibrillary tangle in Alzheimer’s?
Tau becomes hyperphosphorylated which:
- interferes with tau’s ability to bind microtubules leading to disruption of the neuronal cytoskeleton
- self-aggregation of tau into filaments
What are the 2 major components of senile plaques?
- dystrophic processes of neurons in a tangled array [neurites], many of which have phospho-tau
- extracellular deposits of B-amyloid [AB42]
What leads to the abnormal accumulation of B-amyloid in brain parenchyma or cerebral blood vessels [amyloid angiopathy]?
APP [amyloid precursor protein] gene is mutated leading to:
- pathologic cleavage of AB
- decreased clearance of B-amyloid
- combination
What 2 stains can be used in cerebral cortical sections to demonstrate amyloid angiopathy?
- Thioflavin-S will show up neon yellow
2. AB-IHC = antibody to parenchymal and leptomeningial vessels
What feature of Alzheimer’s is the best correlate to cognitive impairment?
The loss of synapses NOT the loss of bulk neurons from the brain.
Where are the following neurons located?
- cholinergic
- SSTergic
- noradrenergic
- serotoninergic
- dopaminergic
- basal forebrain nuclei
- intrinsic cortical nuclei
- locus ceruleus
- raphe in midbrain/pons
- substantia nigra [pc]
In what lobes of the brain are neurofibrillary tangles and senile plaques most abundant?
- medial temporal lobe
- hippocampus - neocortex
[areas of memory and cognition]
How do you make the neuropathologic distinction between the occurrence of neurofibrillary tangles and senile plaques of “normal aging” and AD?
Quantity and distribution
Most likely, it is a continuum from normal aging–> early AD–> classic AD
entorhinal cortex–> limbic–> neocortex
What percent of Alzheimer’s cases are familial? What is the inheritance pattern?
What are the 3 causative genes and what chromosomes are they on?
only 10% are familial
Inheritance = AD for AD
- Presenilin 1 - chromosome 14
- Presenilin 2 - chromosome 1
- APP - chromosome 21
What is the relationship between APOE (chrom 19) and Alzheimer’s?
APOE2 = decreased risk APOE4 = increased risk
What environmental factors have been linked to increased incidence of Alzheimer’s?
- aluminum
2. pesticides
How does Idiopathic Lewy Body Parkinson disease differ from Alzheimer’s in terms of prevalence and presentation?
It has 1/10 the prevalence of AD and affects a younger age group [<60]
Presentation: iPD is a movement disorder : - resting tremor -shuffling gait/stooped posture - rigidity - bradykinesia - bradyphrenia - masked face
What is the pathophysiology behind iPD?
What is seen grossly/histologically?
Selective loss of pigmented neurons in the substantia nigra of the midbrain
Gross: pale instead of dark brown/black
Histologic:
Lewy bodies - round, eosinophilic cytoplasmic inclusions surrounded by a pale halo in the remaining pigmented nuclei [can be up to 6 LB per neuron]
What protein is found in large amounts in Lewy bodies?
a-synuclein
What causes the movement disorder associated with iPD?
Loss of dopaminergic neurons from the substantia nigra.
Typically they project to the basal ganglia [putamen] to activate the direct pathway for movement and damp down the indirect pathway.
Lack of dopamine = lack of movement/coordination of movement
What are the genetic factors that have been identified to cause iPD?
- a-synuclein
- parkin
- PTEN induced putative kinase
- dardarin
- DJ-1
What are the environmental factors associated with iPD?
- MPTP - from contaminated street heroin
- pesticides
- herbicides
- heavy metals
- solvents
A patient is found to have Lewy bodies in the neurons of the cerebral cortex. How did this likely occur?
What is the disease?
This is seen in Lewy body Dementia.
It is likely due to a rostral extension of Parkinson disease-related pathology.
Lewy neurites - abnormal a-synuclein rich neuronal processes occur in grey matter at several locations
What differentiates Lewy Body dementia from AD and iPD?
It has neocortical Lewy bodies, Lewy neurites and concomitant AD.
It presents with early hallucinations and REM behavioral disorders
How is the definitive diagnosis of dementia with lewy bodies made?
There is no clinical test to verify the present of Lewy body pathology so most often it is confirmed at autopsy
What name is given if there is lewy body-type pathology in the brainstem and neocortex?
What name is given if there is AD pathology as well?
a-synuclein = diffuse lewy body disease
lewy bodies/neurites and tau/ab = lewy body variant of AD
What is the difference between primary and secondary loss of myelin?
Secondary : axons have a trophic influence on their myelin sheath. If an axon disintegrates due to motor neuron degeneration or transection, the myelin around the axon will also disintegrate.
Primary:
- dysmyelinating = inborn error of metabolism–> poor synthesis or degradation of myelin
- melinoclastic = myelin is normal but is attacked by disease
What is the difference between dysmyelinating and myelinoclastic primary demyelinating disorders?
Dysmyelinating:
- leukodystophies
- metabolic derangement affects enzymes responsible for synthesis or turnover of myelin
- biochemically abnormal myelin
Myelinoclastic:
- MS
- myelin is attacked by disease process [immune, infectious, toxic]
- biochemically and structurally normal
Why is the the loss of function associated with demyelinating disorders typically permanent?
The axon is generally spared, however, the CNS has a very limited capacity to regenerate myelin
What are the clinical features of demyelination?
- interruption of saltatory conduction
- slight secondary axonal injury –> interrupted conduction of AP
*primarily motor in nature
For Krabbe disease, what is the:
- age of onset
- inheritence pattern
- enzyme deficiency
- toxic agent
- infant or newborn
- AR
- galactocerebroside-B-galactosidase
- galactosyl-sphingoside
For Adrenoleukodystrophy, what is the:
- age of onset
- inheritance pattern
- enzyme def
- toxic agent
- infant—>adolescent
- X-linked R
- ABCD1
- VLCFA
[typically fatal]
For adrenomyeloneuropathy, what is the:
- age of onset
- inheritance pattern
- enzyme def
- toxic agent
- adulthood [affects spinal cord/peripheral nerves]
- XR
- ABCD1
- VLCFA
For metachromatic leukodystophy, what is the:
- age of onset
- inheritance pattern
- enzyme def
- toxic agent
- infancy[fatal], children–>adulthood
- AR
- arylsulfatase A
- sulfatides
Usually demyelination associated with leukodystophy is widespread throughout the white matter and confluent. What is the only white matter spared?
U-fibers that connect adjacent gyri
Describe the onset and presentation of MS.
MS has lesions that develop “over time and space”.
There will be attacks of demyelination that are episodic in nature followed by periods of remission.
*periods of remission increase over the course of the disease and relapses decrease in frequency
How do the demyelinating lesions differ for leukodystrophies and MS?
Leukodystrophy = widespread, confluent, spared U fibers
MS = multifocal, located throughout CNS, mostly periventricular, optic tracts, brainstem, cerebellum, spinal cord
Describe the gross appearance of demyelination of MS.
- sharply demarcated from adjacent white matter [discrete borders are due to loss of myelin and glial fibers causing scarring]
- variable in size
- asymmetric distribution
Microscopically, what is seen with MS?
- small foci of demyelination tend to be around venules
- plaques have lymphocytes and histiocytes
- later on, plaque becomes gliotic with prominent astrocytic processes
Describe the proposed pathogenesis of MS.
- CD4 T cells react with myelin antigens like myelin basic protein [only in CNS myelin]
- demyelination caused by activated macrophages
- CD8 T cells are in active lesions
What region of the world is most affected by MS?
What HLA type is it associated with?
It is strongly genetic [15x for first degree relative]
It affects mostly Canada, US, Northern Europe
HLA-DR2
What lab examinations are useful for diagnosis of MS?
- myelin basic protein in the CSF during active demyelination
- increased CSF IgG
- oligoclonal bands of Ig in the CSF
- MRI to ID white matter lesions in MS
