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Neuro Exam 3 > Neurodegenerative Disorders > Flashcards

Neurodegenerative Disorders Flashcards

1
Q

review of protein folding

A

*newly synthesized proteins folded in ER
-chaperoned by heat-shock proteins
-aid in proper folding, assist in transport (ER, golgi, mitochondria, etc)

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2
Q

ER stress: unfolded protein cell response

A

*cell tries to restore protein homeostasis
*detection of excess abnormally folded proteins leads to:
-decreased protein synthesis
-concurrent increase in chaperone proteins
*if response inadequate (ER stress) -> actively signals apoptosis

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3
Q

ER stress

A

*protein folding DEMAND > protein folding CAPACITY
*leads to failure of adaptation and subsequent apoptosis

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4
Q

proteinopathies

A

*progressive damage to neuronal groups due to accumulation of abnormal protein
*classifications:
1. symptomatic/anatomic classification (specific anatomical regional signs/symptoms)
2. pathological classification (based on protein/inclusion structures)

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5
Q

neurodegeneration of cerebral cortex & hippocampus

A

*Alzheimer disease
*cognitive changes that progress to dementia

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6
Q

neurodegeneration of basal ganglia

A

*Parkinson, Huntington
*movement disorders, hypokinetic or hyperkinetic

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7
Q

neurodegeneration of cerebellum

A

*spinocerebellar ataxias
*disorders of balance (ataxia)

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8
Q

neurodegeneration of spinal cord motor systems

A

*ALS
*limb weakness and difficulty with swallowing and breathing

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9
Q

pathogenesis of neurodegenerative diseases

A
  1. proteins from insoluble aggregates/inclusions
    -mutations -> protein prone to aggregation and resistant to proteolysis
    -protein clearance defects -> gradual accumulation of proteins
  2. small aggregates are neurotoxic
    -trigger unfolded protein response -> apoptotic cell death
    -lead to loss of function of protein
    -may impair gene transcription or protein synthesis

*large aggregates are visible as inclusion bodies
-aberrant localization/sequestration within neurons
-morphologic diagnostic hallmarks

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10
Q

Alzheimer disease - overview

A

*degenerative disease of cortex
*accumulation of β-amyloid (Aβ) and tau protein in specific brain regions

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11
Q

Alzheimer disease - early onset familial genetics

A

mutations in APP cleavage enzymes; presenilin 1/2 genes

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12
Q

Alzheimer disease - late onset familial genetics

A

apoplipoprotein E (ApoE allele epsilon 4) strong influence increased risk

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13
Q

Alzheimer disease & Down syndrome

A

*increased risk/occurrence with Down syndrome
*extra copy of APP on chromosome 21

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14
Q

Alzheimer disease - pathogenesis

A

*accumulation of β-amyloid (Aβ) and tau protein in specific brain regions
*PLAQUES AND NEUROFIBRILLARY TANGLES

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15
Q

Alzheimer disease - pathogenesis of PLAQUES

A

*EXTRAcellular aggregated β-amyloid peptides
*APP cleavage -> extracellular β-amyloid oligomer fibrils
*disrupt synapses, elicits microglia/astrocyte response
*may form around vessels, leading to increased parenchymal hemorrhage

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16
Q

Alzheimer disease - pathogenesis of NEUROFIBRILLARY TANGLES

A

*INTRAcellular aggregates of microtubule binding protein tau
*hyperphosphorylation leads to intracellular aggregates and dystrophic neurites
*disrupt microtubule function
*elicit stress response -> apoptotic neuronal death

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17
Q

Alzheimer disease - epidemiology

A

*most common cause of dementia in older adults
*incidence increases with age (AGE IS THE MOST IMPORTANT RISK FACTOR)
*prevalence doubles every 5 years
*25% genetic predisposition: early onset familial form vs. late-onset familial form; increased risk w/ Down syndrome

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18
Q

Alzheimer disease - clinical features

A

*memory loss; impaired higher intellectual function
*altered mood and behavior
*apraxia (loss of previously learned motor tasks, such as dressing or using eating utensils)
*agnosia (poor processing of sensory info, such as inability to recognize faces or voices as familiar)
*over time, disorientation & aphasia develop
*final phases are profoundly disabled, often mute, and immobile

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19
Q

Alzheimer disease - plaques (simplified)

A

*extracellular
*β-amyloid aggregates

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20
Q

Alzheimer disease - tangles (simplified)

A

*intracellular
*tau aggregates

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21
Q

Alzheimer disease - common causes of death

A

*usually pneumonia or other infections

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22
Q

Alzheimer disease - pathologic findings

A

*diffuse cortical atrophy (narrowing of gyri, widening of sulci, dilation of ventricles hydrocephalus ex vacuo)
*neuritic plaques (extracellular β-amyloid aggregates)
*neurofibrillary tangles (intracellular tau aggregates)

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23
Q

frontotemporal lobar degeneration (FTLD) - overview

A

disorders associated with focal degeneration of frontal and/or temporal lobes

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24
Q

frontotemporal lobar degeneration (FTLD) - etiology

A

*heritable and sporadic variants
1. FTLD tau variants: mutations in MAPT (tau gene)
2. FTLD-TDP variants: hexanucleotide repeats of C9orf72 (most common) - same as ALS

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25
Q

frontotemporal lobar degeneration (FTLD) - clinical manifestation

A

*adult-onset progressive neurodegenerative syndromes
*related to site of neuronal loss:
-frontal lobe = behavior disturbances, cognitive impairment
-temporal lobe = language difficulties
*global dementia may occur with progressive disease

*note - there can be overlap between ALS and FTLD

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26
Q

frontotemporal lobar degeneration (FTLD) - pathology

A

*atrophy and neuronal loss and gliosis of frontal/temporal lobes; aggregation of either of the following:
1. TDP-43 protein = characteristic needle-like inclusions
2. tau protein = neurofibrillary tangles
*ABSENT β-amyloid deposits

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27
Q

FTLD: Pick’s Disease

A

*subtype of FTLD-tau
*severe asymmetric frontotemporal atrophy (reducing gyri to wafer-thin or knife-efge appearance; sparing of posterior 2/3 of superior temporal gyrus)
*neuronal loss and gliosis (surviving neurons show swelling Pick bodies = Tau+ round intracytoplasmic inclusions)
*behavioral and language symptoms arise early

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28
Q

Parkinson disease - overview

A

*degenerative disease caused by loss of dopaminergic neurons from the substantia nigra

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29
Q

Parkinson disease - etiology

A

*common disorder of aging (2% of adults)
*most cases sporadic; rare familial forms

30
Q

Parkinson disease - pathogenesis

A

*α-synuclein aggregates (Lewy Bodies)
*neurons damaged by loss of protein function or toxic accumulated misfolded proteins
*degeneration of dopaminergic neurons of substantia nigra

31
Q

Parkinson disease - clinical features

A

*triad:
1. tremor - “pill-rolling,” resting
2. rigidity - causing postural instability and gait difficulties
3. bradykinesia - gradual and progressive slowing of movement
*absence of toxic or other known underlying etiology
*dementia in late stages
*confirmed by symptomatic response to L-DOPA replacement therapy

32
Q

Parkinson disease - pathologic findings

A

*pallor of substantia nigra and locus ceruleus (loss of pigmented neurons)
*Lewy bodies - composed of α-synuclein; predominantly found in dopaminergic neurons of substantia nigra
*Lewy neurites
*areas of neuronal show gliosis

33
Q

Huntington disease - overview

A

movement disorder caused by degeneration of the caudate and putamen GABAergic neurons

34
Q

Huntington disease - etiology

A

*autosomal dominant: expanded CAG repeats in HTT gene (4p16.3)
*paternal transmission anticipation: further expansions of repeats occur during spermatogenesis (associated with earlier onset of disease in next generation)
*NO sporadic form known

35
Q

Huntington disease - pathogenesis

A

*increased glutamine-encoding CAG trinucleotide repeats in Huntingtin gene
*toxic gain-of-function protein with poorly defined mechanisms of neuronal injury
*mutant protein undergoes proteolysis to generate fragments that form intranuclear ubiquinated aggregates

36
Q

Huntington disease - clinical features

A

*chorea (involuntary, jerky, writhing movements) of all parts of body
*early cognitive sx: forgetfulness and thought & affective disorders
*late cognitive sx: progression to severe dementia
*relentlessly progressive

37
Q

Huntington disease - pathologic findings

A

*dramatic atrophy of caudate & putamen nuclei (symmetric lateral ventricular dilation, loss of GABA neurons, gliosis)
*intranuclear inclusions of ubiquitinated HTT protein

38
Q

amyotrophic lateral sclerosis (ALS) - overview

A

*degeneration of motor neurons in the spinal cord, brainstem, and motor cortex, resulting in muscle weakness and spasticity
*upper motor neuron loss in cerebral cortex AND lower motor neuron loss in anterior horns of spinal cord

39
Q

amyotrophic lateral sclerosis (ALS) - etiology

A

*90% of cases are sporadic
*familial forms - autosomal dominant (C9orf72 or SOD-1)

40
Q

amyotrophic lateral sclerosis (ALS) - clinical features

A

*UMN loss: spasticity, abnormally brisk deep tendon reflexes, Babinski sign
*LMN loss: asymmetric weakness, fasciculations, atrophy in muscles, brainstem dysfunction, respiratory failure
*eventually involves respiratory muscles, leading to death from respiratory failure/pneumonia
*NO sensory loss

*note - there can be overlap between ALS and FTLD

41
Q

amyotrophic lateral sclerosis (ALS) - pathologic findings

A

*intranuclear inclusions:
-Bunina bodies (rope-like inclusions)
-TDP-43 inclusions
*degeneration of motor neurons and reactive gliosis (loss of neurons in spinal cord anterior horns; spinal cord atrophy, loss of myelinated fibers)
*atrophic skeletal muscles

42
Q

spinocerebellar ataxias - overview

A

*trinucleotide repeat expansions in various genes leading to neuronal degeneration in different regions of the brain
*heterogenous, typically autosomal dominant disorders
*polyglutamine expansions (CAG) affecting different proteins
*typically present in middle age

43
Q

Friedrich ataxia - etiology

A

*autosomal recessive
*GAA repeat expansions, frataxin gene

44
Q

Friedrich ataxia - pathology

A

*mitochondrial dysfunction with increased oxidative damage
*involvement of spinocerebellar tract, corticospinal tract, and posterior columns

45
Q

Friedrich ataxia - clinical features

A

*gait ataxia
*sensory peripheral neuropathy
*weakness
*spasticity
*hypertrophic cardiomyopathy
*diabetes
*sclerosis

46
Q

Prion diseases - overview

A

*rapidly progressive neurodegenerative disorders caused by aggregation and intercellular spread of misfolded Prion Protein (PrP)

47
Q

prion disease - pathogenesis

A

*normal PrPc undergoes protease-resistant misfolding, forming PrPSC (may be spontaneous or genetic)
*abnormally folded PrPSC induces conformational changes in other, normal PrPc, accumulating in neural tissue and causing progressive neural damage

48
Q

prion disease - pathologic findings

A

*spongiform encephalopathy (vacuolated neurons; brain tissue neuropil has sponge-like appearance)
*Kuru plaques = aggregates of PrPSC

49
Q

Creutzfeldt-Jakob disease

A

*most common prion disease
*presents as rapidly progressive dementia
*associated with pronounced startle myoclonus
*uniformly fatal
*3 etiologic forms:
-sporadic (majority of cases)
-inherited (mutations in PRNP)
-acquired (iatrogenic transmission)

50
Q

Alzheimer disease - region mainly affected

A

cerebral cortex, hippocampus

51
Q

Alzheimer disease - protein aggregates

A

*β-amyloid (Aβ) plaques (extracellular)
*tau tangles (intracellular)

52
Q

Alzheimer disease - neurologic deficits (simplified)

A

dementia

53
Q

frontotemporal lobar degeneration (FTLD) - region mainly affected

A

frontal and temporal lobes

54
Q

frontotemporal lobar degeneration (FTLD) - protein aggregates

A

*Tau (pick bodies)
OR
*TDP-43 inclusions

55
Q

frontotemporal lobar degeneration (FTLD) - neurologic deficits (simplified)

A

behavioral changes; dementia

56
Q

Parkinson disease - region mainly affected

A

substantia nigra

57
Q

Parkinson disease - protein aggregates

A

α-synuclein

58
Q

Parkinson disease - neurologic deficits (simplified)

A

hypokinetic movement disorder; dementia (late)

59
Q

Huntington disease - region mainly affected

A

caudate nucleus > putamen > cortex

60
Q

Huntington disease - protein aggregates

A

Huntingtin intranuclear inclusions

61
Q

Huntington disease - neurologic deficits (simplified)

A

hyperkinetic movement (chorea); dementia

62
Q

spinocerebellar ataxias - region mainly affected

A

cerebellar cortex, spinal cord, and other regions

63
Q

spinocerebellar ataxias - protein aggregates

A

*various proteins with intranuclear inclusions

64
Q

spinocerebellar ataxias - neurologic deficits (simplified)

A

ataxia (balance disorder)

65
Q

amyotrophic lateral sclerosis - region mainly affected

A

anterior roots of spinal cord

66
Q

amyotrophic lateral sclerosis - protein aggregates

A

*Bunina bodies
*SOD-1
*TDP-43

67
Q

amyotrophic lateral sclerosis - neurologic deficits (simplified)

A

*progressive weakness and paralysis
*UMN and LMN sx
*NO sensory loss

68
Q

prion diseases - region mainly affected

A

cerebral cortex

69
Q

prion diseases - protein aggregates

A

PrP (kuru plaques)

70
Q

prion diseases - neurologic deficits (simplified)

A

rapidly progressive dementia

Neuro Exam 3 (31 decks)

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