Neurodegenerative Disorders

Question 1

review of protein folding

Answer 1

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

Question 2

ER stress: unfolded protein cell response

Answer 2

*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

Question 3

ER stress

Answer 3

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

Question 4

proteinopathies

Answer 4

*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)

Question 5

neurodegeneration of cerebral cortex & hippocampus

Answer 5

*Alzheimer disease
*cognitive changes that progress to dementia

Question 6

neurodegeneration of basal ganglia

Answer 6

*Parkinson, Huntington
*movement disorders, hypokinetic or hyperkinetic

Question 7

neurodegeneration of cerebellum

Answer 7

*spinocerebellar ataxias
*disorders of balance (ataxia)

Question 8

neurodegeneration of spinal cord motor systems

Answer 8

*ALS
*limb weakness and difficulty with swallowing and breathing

Question 9

pathogenesis of neurodegenerative diseases

Answer 9

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

Question 10

Alzheimer disease - overview

Answer 10

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

Question 11

Alzheimer disease - early onset familial genetics

Answer 11

mutations in APP cleavage enzymes; presenilin 1/2 genes

Question 12

Alzheimer disease - late onset familial genetics

Answer 12

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

Question 13

Alzheimer disease & Down syndrome

Answer 13

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

Question 14

Alzheimer disease - pathogenesis

Answer 14

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

Question 15

Alzheimer disease - pathogenesis of PLAQUES

Answer 15

*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

Question 16

Alzheimer disease - pathogenesis of NEUROFIBRILLARY TANGLES

Answer 16

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

Question 17

Alzheimer disease - epidemiology

Answer 17

*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

Question 18

Alzheimer disease - clinical features

Answer 18

*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

Question 19

Alzheimer disease - plaques (simplified)

Answer 19

*extracellular
*β-amyloid aggregates

Question 20

Alzheimer disease - tangles (simplified)

Answer 20

*intracellular
*tau aggregates

Question 21

Alzheimer disease - common causes of death

Answer 21

*usually pneumonia or other infections

Question 22

Alzheimer disease - pathologic findings

Answer 22

*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)

Question 23

frontotemporal lobar degeneration (FTLD) - overview

Answer 23

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

Question 24

frontotemporal lobar degeneration (FTLD) - etiology

Answer 24

*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

Question 25

frontotemporal lobar degeneration (FTLD) - clinical manifestation

Answer 25

*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

Question 26

frontotemporal lobar degeneration (FTLD) - pathology

Answer 26

*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

Question 27

FTLD: Pick's Disease

Answer 27

*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

Question 28

Parkinson disease - overview

Answer 28

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

Question 29

Parkinson disease - etiology

Answer 29

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

Question 30

Parkinson disease - pathogenesis

Answer 30

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

Question 31

Parkinson disease - clinical features

Answer 31

*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

Question 32

Parkinson disease - pathologic findings

Answer 32

*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

Question 33

Huntington disease - overview

Answer 33

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

Question 34

Huntington disease - etiology

Answer 34

*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

Question 35

Huntington disease - pathogenesis

Answer 35

*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

Question 36

Huntington disease - clinical features

Answer 36

*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

Question 37

Huntington disease - pathologic findings

Answer 37

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

Question 38

amyotrophic lateral sclerosis (ALS) - overview

Answer 38

*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

Question 39

amyotrophic lateral sclerosis (ALS) - etiology

Answer 39

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

Question 40

amyotrophic lateral sclerosis (ALS) - clinical features

Answer 40

*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

Question 41

amyotrophic lateral sclerosis (ALS) - pathologic findings

Answer 41

*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

Question 42

spinocerebellar ataxias - overview

Answer 42

*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

Question 43

Friedrich ataxia - etiology

Answer 43

*autosomal recessive *GAA repeat expansions, frataxin gene

Question 44

Friedrich ataxia - pathology

Answer 44

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

Question 45

Friedrich ataxia - clinical features

Answer 45

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

Question 46

Prion diseases - overview

Answer 46

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

Question 47

prion disease - pathogenesis

Answer 47

*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

Question 48

prion disease - pathologic findings

Answer 48

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

Question 49

Creutzfeldt-Jakob disease

Answer 49

*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)

Question 50

Alzheimer disease - region mainly affected

Answer 50

cerebral cortex, hippocampus

Question 51

Alzheimer disease - protein aggregates

Answer 51

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

Question 52

Alzheimer disease - neurologic deficits (simplified)

Answer 52

dementia

Question 53

frontotemporal lobar degeneration (FTLD) - region mainly affected

Answer 53

frontal and temporal lobes

Question 54

frontotemporal lobar degeneration (FTLD) - protein aggregates

Answer 54

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

Question 55

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

Answer 55

behavioral changes; dementia

Question 56

Parkinson disease - region mainly affected

Answer 56

substantia nigra

Question 57

Parkinson disease - protein aggregates

Answer 57

α-synuclein

Question 58

Parkinson disease - neurologic deficits (simplified)

Answer 58

hypokinetic movement disorder; dementia (late)

Question 59

Huntington disease - region mainly affected

Answer 59

caudate nucleus > putamen > cortex

Question 60

Huntington disease - protein aggregates

Answer 60

Huntingtin intranuclear inclusions

Question 61

Huntington disease - neurologic deficits (simplified)

Answer 61

hyperkinetic movement (chorea); dementia

Question 62

spinocerebellar ataxias - region mainly affected

Answer 62

cerebellar cortex, spinal cord, and other regions

Question 63

spinocerebellar ataxias - protein aggregates

Answer 63

*various proteins with intranuclear inclusions

Question 64

spinocerebellar ataxias - neurologic deficits (simplified)

Answer 64

ataxia (balance disorder)

Question 65

amyotrophic lateral sclerosis - region mainly affected

Answer 65

anterior roots of spinal cord

Question 66

amyotrophic lateral sclerosis - protein aggregates

Answer 66

*Bunina bodies *SOD-1 *TDP-43

Question 67

amyotrophic lateral sclerosis - neurologic deficits (simplified)

Answer 67

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

Question 68

prion diseases - region mainly affected

Answer 68

cerebral cortex

Question 69

prion diseases - protein aggregates

Answer 69

PrP (kuru plaques)

Question 70

prion diseases - neurologic deficits (simplified)

Answer 70

rapidly progressive dementia