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NS2 Test 2 > Chapter 28 part 4 > Flashcards

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
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2
Q

when do prio diseases occur?

A
  • PrP undergoes a conformational change- PrPsc
  • acquires resistance to digestion with proteases
  • gene encoding PrP- PRNP
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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
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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

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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
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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
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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)
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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

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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
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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
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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
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12
Q

inactive plaque

A
  • little to no myelin found
  • reduction in number of oligodendrocytes nuclei
  • astrocytic proliferation and gliosis
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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
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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
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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
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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
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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
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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
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19
Q

central pontine myelinolysis clinincal features

A
  • rapidly evolving quadriplegia
  • locked in syndrome- fully conscious yet unresponsive
  • hyponatremia needs to be corrected slowly
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20
Q

the pathologic process that is common across most of the neurodegenerative diseases is?

A

-accumulation of protein aggregates

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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
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22
Q

neurodegenerative diseases-2 approaches

A
  • symptomatic/anatomic

- pathologic-types of inclusions

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23
Q

most common cause of dementia

A

Alzheimers disease

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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
Q

fundamental abnormality in AD is?

A

-accumulation of 2 proteins- Ab and tau

26
Q

2 hallmarks of AD

A
  • plaques- aggregated AB peptides in neutropil

- tangles- aggregates of microtubule binding protein tau

27
Q

what is the critical initiating event for the development of AD?

A

-AB generation

28
Q

Role of AB/how is it made?

A
  • 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
Q

role of tau

A
  • 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
Q

other genetic risk factors for AD

A
  • 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
Q

AD-role of inflammation

A

-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
Q

AD basis for cognitive impairment

A
  • plaques and tangles–associated with severe cognitive dysfunction
  • neurofibrillary tangles–correlates better with degree of dementia
33
Q

AD biomarkers

A
  • can image AB deposition on brian

- increased phosphorylated tau and reduced AB in CSF

34
Q

AD gross morphology

A

-cortical atrophy-widening of cerebral sulci, ventricular enlargement (hydrocephalus ex vacuo)

35
Q

AD morphology microscopic

A

-neuritic plaques and neurofibrillary tangles (neuronal loss and reactive gliosis)

36
Q

neuritic plaques

A
  • 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
Q

diffuse plaques

A

-when deposition of AB peptides in absence of surrounding neuritic processes

38
Q

neurofibrillary tangles

A
  • 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
Q

cerebral amyloid angiopathy

A
  • can be found in brains without AD

- AB40 predominantly

40
Q

AD clinincal features

A
  • 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
Q

FTLDs (Frontotemporal lobal degenerations)

A
  • focal degeneration of frontal and/or temporal lobes
  • global dementia occurs with progression–frontotemporal dementia
  • occurs under age 65
42
Q

FTLD-distinguished from AD how?

A

-personality, behavior, language precede memory loss!!

43
Q

FTLD-cellular inclusions

A
  • tau containing inclusions (FTLD-tau)

- TDP43 containing inclusions (FTLD-TDP)

44
Q

FTLD-Tau

A
  • 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
Q

FTLD- Tau–2 diff tau mutations

A
  • missense point mutation- causes Tau phosphorylation

- point mutations- affects splicing–enhances Tau aggregation

46
Q

FTLD tau morphology

A
  • atrophy of frontal and temporal lobes

- atrophic regions-neuronal loss, gliosis, tau containing neurofibrillary tangles

47
Q

Pick disease

A
  • 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
Q

FTLD-tau morphology microscopic

A
  • 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
Q

FTLD-TDP

A
  • inclusions of TDP43 RNA binding protein

- behavior or language compaints

50
Q

FTLD-TDP–3 genetic forms

A
  • 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
Q

TDP43 in disease?

A
  • normally found diffusely in nucleus

- in disease– inclusions in cell body, nucleus or in neurites–TDP43 phosphorylated and ubiquinated

52
Q

PD (parkinsons disease) marked by?

A
  • prominent hypokinetic movement disorder

- caused by loss of dopaminergic neurons from the substantia nigra

53
Q

PD clinical syndrome

A

-diminished facial expression (masked facies), stooped postures, slowing of voluntary movement, festinating gait (shortened, accelerate steps), rigidity, pill rolling tremor

54
Q

prinicipal degenerative disease that involves the nigrostriatal system?

A

PD

55
Q

PD diagnosis (central triad)

A
  • tremor, rigidity, bradykinesia
  • confirmed by symptomatic response to L-dopa replacement therapy
  • lewy body
56
Q

PD genetic causes

A
  • 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
Q

PD morphology–characteristic finidng

A
  • pallor of substantia nigra (due to loss of pigmented, catecholaminergic neurons)
  • lewy bodies found in some remaining neurons
58
Q

lewy bodies

A
  • 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
Q

dementia with lewy bodies–characteristic features

A
  • 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

NS2 Test 2 (16 decks)

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