Chapter 28: Demyelinating/Neurodegenerative Diseases/Toxic and Acquired Metabolic Diseases Flashcards
Demyelinating diseases of the CNS are acquired conditions characterized by preferential damage to ________ w/ relative preservation of ______.
Demyelinating diseases of the CNS are acquired conditions characterized by preferential damage to myelin w/ relative preservation of axons.
Why is severe cognitive impairment not a usual feature of MS?
Gray matter is relatively spared
Which disease is characterized by distinct episodes of neuro deficits separated in time due to white matter lesion that are separated in space
Multiple Sclerosis
Which MHC halotype increases risk for developing MS?
HLA-DR2
Which T cells are the major players in causing damage to the myelin in persons w/ MS?
CD4+ TH1 and TH17
Which demyelinating disease is associated with lesions that are firmer than the surrounding white matter and contain circumscribed, depressed, glassy, grey-tan, irregularly shaped plaques?
MS
What is seen morphologically in an active plaque of a patient with MS?
- Abundant macrophagescontaininglipid-rich, PAS-positive debris
- Perivascular (small veins) inflammatory infiltrate (mononuclear) at outer edge of plaqe
- Relative preservation of axons within plaque and depletion of oligodendrocytes
A 40 yo woman who presents with chief complaint of unilateral disturbance should raise red flags for which disease until proven otherwise?
MS
What is a frequent initial manifestation of MS?
Unilateral visual disturbances due to involvement of the optic nerve (optic neuritis, retrobulbar neuritis)
The mnemonic for MS is SINS, what are each of these clinical findings?
S = scanning speech
I = intention tremor (incontinence and INO)
N = nystagmus
Internculear opthalmoplegia (INO) often seen in MS is due to damage to what?
Medial longitudinal fasciculus (MLF)
Which Ig is found in increased levels in the CSF of patients with MS?
What is seen on immunoelectrophoresis?
- IgG
- Oligoclonal IgG bands
Infarction of which artery is associated with contralateral homonymous hemianopia?
Posterior Cerebral Artery
Infarction of which artery is associated with UMN-type weakness and cortical-type sensory loss; contralateral hemiplegia initially?
Anterior Cerebral Artery (ACA)
What is the significance of Transient Ischemic Attacks (TIA)?
- Are a warning sign for potentially larger ischemic injury to the brain
- Neurological emergency!
- 15% of TIA pts will have a stroke causing persistent deficits within 3 months; HALF of those within the first 48 hrs
Genes for which interleukin receptors have been associated with an increased risk in developing MS?
IL-2 and IL-7
What are the CSF findings in MS?
- Midly elevated protein
- Moderate pleocytosis in 1/3 cases
- IgG increased
Which condition is characterize by synchronous bilateral optic neuritis and spinal cord demyelination?
Neuromyelitis optica (aka Devic disease)
Neuromyelitis optica is due to antibodies against?
Major channel of which cell?
Aquaporin-4; major water channel of astrocytes
What is commonly found in the CSF of patients with Neuromyelitis Optica?
White cells, often including neutrophils
Although similar to MS, how does Acute Disseminated Encephalomyelitis (ADEM) differ?
When does it occur and what are the clinical manifestations?
- Occurs in younger patients w/ an abrupt onset and may be rapidly fatal
- Is a DIFFUSE monophasic demyelinating disease occuring after a viral infection or viral immunization (rare)
- Signs and symptoms develop 1-2 weeks after the antecedent infection as headache, lethargy, and coma
- In contrast to MS, all of the lesions look similar – monophasic
*MS has focal findings w/ considerable variance in the size of lesions
Acute necrotizing hemorrhagic encephalomyelitis (AKA acute hemorrhagic leukoencephalitis of Weston Hurst) is almost invariable preceded by a recent episode of?
Who is most at risk?
- Upper respiratory infection (URI)
- Young adults and children
Central pontine myelinolysis (aka osmotic demyelination disorder) most commonly arises when?
- 2-6 days after rapid correction of hyponatremia
- Low to high, the pons will die
Which neurodegenerative disorder is characterized by loss of myelin in a roughly symmetric pattern involving the basis pontis and portions of the pontine tegmentum, including myelin loss WITHOUT evidence of inflammation?
Central pontine myelinolysis (aka osmotic demyelination disorder)
What is the clinical presentation of Central pontine myelinolysis (aka osmotic demyelination disorder)?
- Rapidly evolving quadriplegia, which may be fatal
- “Locked-in” syndrome, in which patients are fully conscious yet unresponsive
Following cleavage of APP by either the α-secretase or β-secretase, what is the function of the γ-secreatse complex?
- Performs an intramembranous cleavage
- When paired with first cut by α-secretase, produces a soluble fragment
- When paired with β-secretase cleavage, it generates Aβ (highly prone to aggregation)
Which chromosome is the gene encoding APP located on and why is this significant?
- Chromosome 21
- Lies in the down syndrome region; patients with down syndrome usually develop Alzheimers around age 40
Generation of which peptide aggregates are the critical initiating event for the development of AD?
Aβ first and then tau
Plaques are deposits of aggregated ______ peptides in the _______
Tangles are aggregates of the ________ binding protein tau
Plaques are deposits of aggregated Aβ peptides in the neuropil
Tangles are aggregates of the microtubule binding protein tau
Which 3 diseases do Tau deposits appear in without the appearance of Aβ?
1) Frontotemporal lobar degeneration (Picks disease)
2) Progressive supranuclear palsy
3) Corticobasal degeneration
Which chromosome contains the ApoE locus?
Chromosome 19
A higher number of (plaques/tangles) correlates better with the degree of dementia seen in AD?
Number of neurofibrillary tangles correlates better with the degree of dementia
What are the focal spherical collections of dilated tortous neuritic processes (dystrophic neurites) around an amyloid core seen in AD?
How are they stained?
- Neuritic (senile) plaques
- Amyloid core can be stained w/ congo red; dominant component of amyloid core = Aβ
Grossly how does the brain of a patient with AD look; where are the effects most pronounced?
Which compensatory change is seen?
- Cortical atropy = widening of sulci, narrowing of gyri
- Most pronounced in: frontal, temporal, and parietal lobes
- Compensatory ventricular enlargement –> Hydrocephalus ex vacuo
Which parts of the brain will contain neuritic (senile) plaques associated w/ AD?
Hippocampus, amygdala, and neocortex
Diffuse plaques seen in AD have no _____ and are predominantly made up of Aβ____
Diffuse plaques seen in AD have no amyloid core and are predominantly made up of Aβ 42
Neurofibrillary tangles are seen best with which stain?
Bielschowsky stain (silver stain)
How do neurofibrillary tangles appear in pyramidal neurons vs. in rounder cells?
- Pyramidal = elongated “flame” shape
- Rounder cells = “globose;” basket weave of fibers around nucleus
Structures of which lobe are involved earliest in the AD and are usually severely atrophied in the later stages?
Medial temporal lobe, including hippocampus, entorhinal cortex and amygdala
Neurofibrillary tangles are insoluble and apparently resistant to clearance in vivo, thus remaining visible in tissue sections as _______ or _______ tangles long after the death of the parent neuron.
“Ghost” or “Tombstone” tangles
What are Hirano Bodies and what is their major component?
- Elongated glassy eosinophilic bodies
- Actin = major component
Cerebral amyloid angiopathy (CAA) is an almost invariable accompaniment of _______
AD
The vasuclar amyloid seen in CAA is predominantly of which type?
Aβ40
What is typically the terminal event in a patient with AD?
Intercurrent disease, often pneumonia
How are Frontaltemporal Lobar Degenerations (FTLDs) distinguished from AD in term of clinical manifestations?
Changes in personality, behavior, and language come BEFORE changes in memory
Accumulation of what is seen in FTLD-tau?
- Accumulation of tau and NOT Aβ are characteristic
- Smooth contoured inclusions —> Pick bodies
FTLDs are one of the more common causes of?
Early onset dementia
What is the characteristic pattern of atrophy seen in Pick disease?
- Asymmetric, atrophy of the frontal and temporal lobes w/ sparing of the posterior 2/3 of superior temporal gyrus
- Reduction of gyri to a wafer-thin (“knife-edge”) appearance
What are Pick Cells vs. Pick Bodies?
How do Pick bodies stain?
- Pick cells = swollen cells
- Pick bodies = cytoplasmic, round to oval, filamentous inclusions that are weakly basophilic and stain strongly with silver
Some patients with clinically diagnosed FTLD have inclusions that contain ______, but DO NOT contain Tau
TDP-43
The most common genetic form of FTLD-TDP is the result of an expansion of a _________ repeat in the 5’ UTR of ________
The most common genetic form of FTLD-TDP is the result of an expansion of a hexanucleotide repeat in the 5’ UTR of C9orf72
In FTLD-TDP, there are inclusions containing TDP-43 which is both ______ and ________
In FTLD-TDP, there are inclusions containing TDP-43 which is both phosphorylated and ubiquinated
There is an extremely strong correlation between the presence of needle like neuronal intranuclear inclusions (NII) and which mutation causing FTLD-TDP?
Progranulin mutations
In the absence of a toxic or other known etiology the presumptive diagnosis of PD can be based on the presence of the central triad of parkinsonism, which includes?
How is this diagnosis confirmed?
1) Tremor
2) Rigidity
3) Bradykinesia
- Confirmed by symptomatic response to L-DOPA replacement therapy
Which compound previosuly found in elicit drugs was found to destroy neurons in the substantia nigra and cause an acute parkinsonian syndrome?
MPTP