Chapter 28 part 4 Flashcards
1
Q
etiologic basis of prion disease
A
abnormal forms of prion proteins (PrP)
- spongiform change-caused by intracellular vacuoles in neurons and glia
- clinically- rapidly progressive dementia
2
Q
when do prio diseases occur?
A
- PrP undergoes a conformational change- PrPsc
- acquires resistance to digestion with proteases
- gene encoding PrP- PRNP
3
Q
CJD (creuzfeld-jakob disease)- symptoms, caused by?
A
- most common prion disease
- clinically-rapidly progressive dementia
- familial forms- mutations in PNRP
- onset- changes in memory, behavior, followed by rapidly progressive dementia, involuntary jerking m contractions or sudden stimulation
- cerebellar dysfunction- ataxia
- average survival- 7 months
4
Q
variant creutzfeldt jakob disease- diff from CJD how?
A
-young adults, behavior disorders in early stages of disease, neurologic syndrome progressed more slowly
5
Q
variant CJD- linked to exposure to? characterized by?
A
- bovine spongiform encephalopathy- in contaminated foods or blood transfusion
- present of extensive cortical plaques surrounded by a halo of sponfiform change
- no alterations in PNRP gene
6
Q
FFI (fatal familial insomnia)
A
- sleep disturbances- initial stages
- mutations in PRNP gene
- lasts fewer than 3 years–neurologic signs- ataxia, autonomic disturbances, stupor, coma
7
Q
3 pathologic processes that cause loss of myelin
A
- immune mediated destruction (MS)
- infections (PML- JC virus infection of oligodendrocytes)
- -leukodystrophies (inherited disorders that affect the syn of turnover of myelin components)
8
Q
MS (multiple sclerosis)- characterized by?
A
- autoimmune demyelinating disorder
- characterized by distinct episodes of neurologic deficits, separated in time due to white matter lesions
9
Q
MS lesions caused by?
A
- autoimmune response directed against components of myelin sheath
- initiated by TH1 and Th17 cells that react against antigens and secrete cytokines
- Th1 secrete IFN-y– act macrophages
- Th17-promote recruitment of leukocytes
- demyelination is caused by act leukocytes
10
Q
MS gross morphology
A
- lesions firmer than surrounding white matter (sclerosis)
- lesions appear well circumscribed, depressed glassy, gray-tan, irregularly shaped plaques
- area of demyelination- sharply defined borders
- plaques common adjacent to lateral ventricles and in optic nerves and chiasm, brainstem, ascending and descending fiber tracts, spinal cord, cerebellum
11
Q
MS microscopic morphology
A
- active plaque- ongoing myelin breakdown associated with macrophages containing lipid-rich PAS-positive debris
- lymphocytes and monocytes present as perivascular cuffs
- centered on small vs
- in plaque- preservation of axons, depletion of oligodendrocytes
12
Q
inactive plaque
A
- little to no myelin found
- reduction in number of oligodendrocytes nuclei
- astrocytic proliferation and gliosis
13
Q
shadow plaques
A
- border bw normal and affected white matter is not sharply circumscribed
- some abnormally thinned-out myelin sheaths
- evidence of partial/incomplete remyelination by surviving oligodendrocytes
14
Q
MS clinical features
A
- unilateral visual impairment due to involvement of optic n (optic neuritis, retrobulbar neuritis)- frequent initial sign!!
- brainstem lesions- nystagmus, ataxia, CN sign
- spinal cord lesions- motor and sensory impairment, spasticity, difficulty with voluntary control of bladder function
- CSF- elevated protein level, IgG levels increased
15
Q
NMO (neuromyelitis optica)
A
- bilateral optic neuritis and spinal cord demyelination
- women
- poor recovery after 1st attack
- presence of Ab against aquaporin-5 (major water channel of astrocytes)- abs injure astrocytes through complement dep mechanism
- CSF- white cells
- damaged areas of white matter- necrosis, inflammatory infiltrate, vascular deposition of Ig complement
16
Q
acute disseminated encephalomyelitis clinical course
A
- diffuse, monophasic demyelinating disease- follows a viral infection or rarely a viral immunization
- symptoms- 1-2 wks after infection- headache, lethargy, coma
- clinical course- 20% die, remaining recover completely
17
Q
acute necrotizing hemorrhagic encephalomyelitis (acute hemorrhagic leukoencephalitis of weston hurst)
A
- fulminant syndrome of CNS demyelination, affecting yound adults, children
- preceded a recent episode of upper resp infection
- fatal in many, significant deficits in survivors
18
Q
central pontine myelinolysis
A
- loss of myelin in the basis pontis and portions of pontine tegmentum, in a roughly symmetric pattern
- 2-6 days after rapid correction of hyponatremia or other electrolyte disturbances (also known as osmotic demyelination disroder)
- rapid increases in osmolality damage oligodendrocytes
- no inlammation in lesions, neurons and axons preserved
- lesions appear at the same stage of myelin loss
19
Q
central pontine myelinolysis clinincal features
A
- rapidly evolving quadriplegia
- locked in syndrome- fully conscious yet unresponsive
- hyponatremia needs to be corrected slowly
20
Q
the pathologic process that is common across most of the neurodegenerative diseases is?
A
-accumulation of protein aggregates
21
Q
diagnostic hallmark of neurodegenerative disease?
A
- inclusions!!
- protein aggregates-resistant to degradation, show localization within neuron, elicit a stress response within the cell, often directly toxic to neurons
- toxic gain of function and loss of function- more protein is shunted into aggregates rather than performing normal physiological functions
22
Q
neurodegenerative diseases-2 approaches
A
- symptomatic/anatomic
- pathologic-types of inclusions
23
Q
most common cause of dementia
A
Alzheimers disease
24
Q
AD symptoms
A
- deficits in memory, visuospatial orientation, judgment, personality, language
- 5-10 years- diabled, mute, immobile
- rarely symptomatic before age 50
25
fundamental abnormality in AD is?
-accumulation of 2 proteins- Ab and tau
26
2 hallmarks of AD
- plaques- aggregated AB peptides in neutropil
| - tangles- aggregates of microtubule binding protein tau
27
what is the critical initiating event for the development of AD?
-AB generation
28
Role of AB/how is it made?
- APP (cell surface protein) -AB portion extends from extracellular region into transmembrane domain
- y secretase (intramembranous cleavage)
- if paired with B-secretase cleavage--generates AB
- AB highly prone to aggregation
- familial AD-point mutations in APP
29
role of tau
- microtubule associated protein present in axons
- with development of tangles- Tau shifts to a somatic-dendritic distribution-becomes hyperphosphorylated and loses the ability to bind to microtubules
30
other genetic risk factors for AD
- genetic locus that encodes ApoE-strong influence of risk of A- 3 alleles (apoE2,3,4)
- E4 allele=increased risk of AD, lowers onset of disease
31
AD-role of inflammation
-aggregates of AB elicit inflammatory response from microglia and astrocytes--assits in clearance of aggregated peptide, but also stimulate secretion of mediatiors that cause damage
32
AD basis for cognitive impairment
- plaques and tangles--associated with severe cognitive dysfunction
- neurofibrillary tangles--correlates better with degree of dementia
33
AD biomarkers
- can image AB deposition on brian
| - increased phosphorylated tau and reduced AB in CSF
34
AD gross morphology
-cortical atrophy-widening of cerebral sulci, ventricular enlargement (hydrocephalus ex vacuo)
35
AD morphology microscopic
-neuritic plaques and neurofibrillary tangles (neuronal loss and reactive gliosis)
36
neuritic plaques
- focal, spherical collections of dilated, tortuous, neuritic process (dystrophic neurites) often around a central amyloid core
- microglial cells and reactive astrocytes in periphery
- amyloid core- contains AB (AB40 and AB42)
37
diffuse plaques
-when deposition of AB peptides in absence of surrounding neuritic processes
38
neurofibrillary tangles
- tau containing bundles of filaments in cytoplasm of neurons that displace the nucleus
- elongated, flame shape
- insoluble and resistant to clearance-remain visible in tissue sections as "ghost" tangles after the death of the neuron
39
cerebral amyloid angiopathy
- can be found in brains without AD
| - AB40 predominantly
40
AD clinincal features
- initial-forgetfulness, memory disturbance
- progression-language deficits, loss of math skills, loss of learned motor skills
- final stages- incontinent, mute, unable to walk
- intercurrent disease (pneumonia)- terminal event
- progression slow and relentless- more than 10 years
41
FTLDs (Frontotemporal lobal degenerations)
- focal degeneration of frontal and/or temporal lobes
- global dementia occurs with progression--frontotemporal dementia
- occurs under age 65
42
FTLD-distinguished from AD how?
-personality, behavior, language precede memory loss!!
43
FTLD-cellular inclusions
- tau containing inclusions (FTLD-tau)
| - TDP43 containing inclusions (FTLD-TDP)
44
FTLD-Tau
- neuronal loss and reactive gliosis, along with presence of tau-containing inclusions in neurons
- diff from AD (tau and Ab)- FTLD-Tau only shows tau aggregation
- pink disease--tau inclusions, lobar restriction
45
FTLD- Tau--2 diff tau mutations
- missense point mutation- causes Tau phosphorylation
| - point mutations- affects splicing--enhances Tau aggregation
46
FTLD tau morphology
- atrophy of frontal and temporal lobes
| - atrophic regions-neuronal loss, gliosis, tau containing neurofibrillary tangles
47
Pick disease
- atrophy of frontal and temporal lobes with sparing of the posterior 2/3 superior temporal gyrus
- atrophy can be severe-reducing gyri to water thin (knife edge) appearance
48
FTLD-tau morphology microscopic
- neuronal loss--most severe in outer 3 layers of cortex
- some surviving neurons show swelling (pick cells); others contain pick bodies (cytoplasmic, round to oval, filamentous inclusions)
49
FTLD-TDP
- inclusions of TDP43 RNA binding protein
| - behavior or language compaints
50
FTLD-TDP--3 genetic forms
- expansion of a hexanucleotide repeat in C90rf72
- mutation in gene that encodes TDP43 (Toxic effects)
- mutations in gene that encodes progranulin (loss of function expressed in glia and neurons that is cleaved into small peptides--these peptides involved in region of inflammation in the brain)
51
TDP43 in disease?
- normally found diffusely in nucleus
| - in disease-- inclusions in cell body, nucleus or in neurites--TDP43 phosphorylated and ubiquinated
52
PD (parkinsons disease) marked by?
- prominent hypokinetic movement disorder
| - caused by loss of dopaminergic neurons from the substantia nigra
53
PD clinical syndrome
-diminished facial expression (masked facies), stooped postures, slowing of voluntary movement, festinating gait (shortened, accelerate steps), rigidity, pill rolling tremor
54
prinicipal degenerative disease that involves the nigrostriatal system?
PD
55
PD diagnosis (central triad)
- tremor, rigidity, bradykinesia
- confirmed by symptomatic response to L-dopa replacement therapy
- lewy body
56
PD genetic causes
- most are sporradic
- gene that encodes alpha synuclein (lipid binding protein normally associated with synapses--major component of Lewy body)
- mitochondrial dysfunction (autosomal recessive-mutations in fenes that encode DJ-1, PINK1, parkin)
- mutations in gene encoding LRRK2 (Autosomal dominant--cytoplasmic kinase--gain in function--hyperphosphorylation)
57
PD morphology--characteristic finidng
- pallor of substantia nigra (due to loss of pigmented, catecholaminergic neurons)
- lewy bodies found in some remaining neurons
58
lewy bodies
- cytoplasmic, eosinophilic, round to elongated inclusions that have a dense core surrounded by a pale halo
- composed of fine filaments, densely packed in core but loose at rim
- these filamanets are composed of alpha synuclein
59
dementia with lewy bodies--characteristic features
- 10-15% of patients with PD develop dementia
- fluctuating course, hallucinations, prominent frontal signs
- widespread lewy bodies in neurons in brainstem and cortex
- composed of alpha synuclein
