Demyelinating, Neurodegenerative Diseases Flashcards
1
Q
True or False: demyelinating diseases are acquired conditions that preferentially damage myelin, with relative preservation of axons
A
True
2
Q
True or False: demyelinating diseases can be immunologic or inherited
A
True.
Example: leukodystrophies are inherited; MS is immunologic
3
Q
Describe the temporal and spatial occurrences of the neurological deficits in MS.
A
- episodes of neurological deficits are separated in time
- episodes attributed to separated white matter lesions
- relapsing and remitting episodes of varying duration
- freq. decreases during course
- neuro deterioration, in general, occurs steadily
4
Q
What commons signs and symptoms of MS?
A
- unilateral vision impairment (frequently first symptom)
- -10-15% of pts with optic neuritis develop MS
- brainstem: ataxia, nystagmus
- spinal cord: motor/sensory impairment of trunk/limbs, spasticity, dysfunction of bowel/bladder control
5
Q
How is genetics involved in MS?
A
- -occurrence 15x higher in pts w/ 1st degree relative
- -DR2: genetic linkage of MS susceptibility
- -IL-2 and IL-7 receptor genes
6
Q
Describe the inflammation of MS.
A
–initiated by CD4+ Th1 and Th17 cells secreting cytokines and reacting against self myelin Ag’s
- Th1 secrete IFN gamma to activate macrophages
- Th17 recruit leukocytes
–plaque infiltrate is mainly CD4+ T-cells
7
Q
What is the gross morphology of MS?
A
- multiple circumscribed, slightly depressed, glassy, gray/tan irregularly shaped plaques, commonly adjacent to the lateral ventricles or in the optic nerves
- plaques are sclerosed (firmer than surrounding area)
8
Q
What is the histology of active plaques in MS where myelin breakdown is ongoing?
A
–abundant macrophages that contain lipid-rich, PAS+ debris (myelin)
–mononuclear inflammatory infiltrate located perivascular at the outer edge of the plaque
–depletion of oligodendrocytes, but axons preserved
9
Q
What is the histology of inactive plaques?
A
- inflammatory cells have disappeared
- little to no myelin anymore
- reduced number of oligodendrocytes and axons
- -instead, astrocyte proliferation and gliosis
10
Q
What are the CSF findings in MS patients?
A
- mildly elevated protein
- moderate pleocytosis (increased WBC count in CSF)
- IgG increased
- -oligoclonal IgG bands in gamma region (B cell clones)
11
Q
What is Neuromyelitis Optica?
A
- -B/L optic neuritis and spinal cord demyelination
- -Ab’s against aquaporin-4 (important in astrocytes)
- –however, the foot processes are NOT damaged
- -much more common in females
- -neutrophils, turbid CSF; increased opening pressure
12
Q
What is the treatment for Neuromyelitis Optica?
A
-therapies that target reduction of the Ab load, such as plasmapharesis or an anti-CD20 Ab to deplete B cells
13
Q
What is Acute Disseminated Encephalomyelitis?
A
- a diffuse monophasic demyelinating dz
- follows a viral infection (or rarely, an immunization)
- symptoms: HA, lethargy, coma (non-focal findings)
- 20% die, 80% fully recover
14
Q
What is the morphology of Acute Disseminated Encephalomyelitis (ADEM)?
A
- -gray discoloration around the white matter vessels
- -loss of myelin w/ axons preserved
- -early infiltrates are PMN’s, late are monocytes
- -lipid-laden macrophages d/t myelin breakdown
15
Q
What is Acute Necrotizing Hemorrhagic Encephalomyelitis (ANHE)?
A
- fulminant syndrome of CNS demyelinization
- follows upper respiratory infection
- typically affects children and young adults
- fatal in most; deficits present in survivors
16
Q
What is Central Pontine Myelinolysis (Osmotic Demyelination Syndrome)?
A
-symmetric loss of myelin in the basis pontis and portions of the pontine tegmentum
- no evidence of inflammation
- occurs 2 to 6 days after rapid correction of hypoNa+
17
Q
What are the symptoms of Central Pontine Myelinolysis (Osmotic Demyelination Syndrome)?
A
- -acute paralysis
- -dysphagia and dysarthria
- -diplopia
- -loss of consciousness
- -“locked-in” syndrome
18
Q
What are the major characteristics of neurodegenerative diseases?
A
- -diseases of grey matter, w/ progressive neuron loss
- -affects groups of functionally-related neurons
- -accumulation of protein aggregates (inclusions)
- –aggregates are usually resistant to degradation
19
Q
What is Alzheimer Disease?
A
- -most common cause of dementia in elderly
- -impairment of higher intellectual function
- -alterations in mood and behavior
- -rarely symptomatic prior to age 50 (40% over age 85)
- -most cases are sporadic (only 5-10% familial)
20
Q
What are the symptoms of Alzheimer Disease?
A
- progressive disorientation, memory loss, and aphasia
- become profoundly disabled, mute, and immobile
- cortical atrophy and widened sulci
- frontal, temporal, and parietal lobes
- definitive Dx comes from pathology exam postmortem
21
Q
What are neuritic plaques in the histology of Alzheimer Disease?
A
-focal spherical collections of dystrophic neurites around an amyloid core, which stains with Congo Red and contains abnormal AB40 and AB42 proteins
22
Q
What are diffuse plaques in the histology of Alzheimer Disease?
A
-found mainly in superficial cerebral cortex, basal ganglia, and cerebellar cortex
- no amyloid core
- only contain AB 42
23
Q
What are neurofibrillary tangles in the histology of Alzheimer Disease?
A
- cytoplasmic bundles of filaments containing tau
- displace or encircle nucleus
- found in cortical neurons, hippocampus, amygdala
- shape of the tangle depends on the cell’s shape
- -“flame” in pyramidal neuron; “globose” in round cells
- basophilic in H and E stain
- better seen with silver stain (Bielschowsky)
-resistant to clearance in vivo, leaving “ghost tangles”
24
Q
Which correlates better with the degree of dementia, number of tangles or number of plaques?
A
number of tangles
25
What is granulovacuolar degeneration in the histology of Alzheimer Disease?
- small, clear intraneuronal cytoplasmic vacuoles containing argyrophilic granules
- normal in aging; MORE ABUNDANT in Alzheimer Dz in hippocampus and olfactory bulb
26
What are Hirano Bodies in the histology of Alzheimer Disease?
- elongated, glassy, eosinophilic bodies
- paracrystalline arrays of beaded filaments
- -major component is ACTIN
- present in hippocampal pyramidal cells
27
What is Cerebral Amyloid Angiopathy?
- invariably present in Alzheimer Disease
- -but can be seen outside of Alzheimer Disease
- AB40 amyloid protein (stains w/ Congo Red)
- thick vessel walls
28
What is Pick Disease (rare), one of the Frontotemporal Dementias with tau pathology?
- progressive dementia
| - EARLY ONSET of behavior changes (frontal lobe sign) and language disturbances (temporal lobe sign)
29
What is the morphology of Pick Disease?
- -asymmetric atrophy of frontal and temporal lobes
- -posterior 2/3rds of superior temporal gyrus spared
- -"knife-edge" thin gyri w/ deep and wide sulci
- -Pick Cells (swollen cells)
- -Pick Bodies (cytoplasmic filamentous inclusions, weakly basophilic, stain strongly with silver stain)
30
What is Progressive Supranuclear Palsy?
-widespread neuron loss in globus pallidus, subthalamic nucleus, substantia nigra, dentate nucleus
- onset in 40's-60's, men 2x as likely as women
- fatal within 5-7 years
-globose neurofibrillary tangles made of 4R tau straight filaments
31
What are the symptoms of Progressive Supranuclear Palsy?
-TRUNCAL RIGIDITY w/ dysequilibrium and nuchal dystonia
- abnormal speech
- ocular disturbances (vertical gaze palsy)
- mild progressive dementia
32
What is Vascular Dementia, a progressive cognitive disorder that is associated w/ vascular injury?
--improves w/ Tx if d/t vasculitis
- widespread areas of infarction (cortical microinfarcts, lacunar infarcts, cortical laminar necrosis)
- diffuse white matter injury (HTN, CADASIL aka Cerebral Autosomal Dominant Arteriopathy w/ Subcortical Infarcts and Leukoencephalopathy)
- strategic infarcts (usually embolic): hippocampus, dorsomedial thalamus or cingulate gyrus
33
What category of disorders are associated with degenerative diseases of the basal ganglia and brainstem?
movement disorders
-rigidity, abnormal posturing, chorea
-basal ganglia (esp. nigrostriatal pathway) plays a role in modulating feedback from thalamus to motor cortex
34
What are the symptoms of Parkinson Disease?
- DIMINISHED FACIAL EXPRESSION
- stooped posture
- SLOWNESS of voluntary mvmt
- festinating gait (accelerated steps)
- rigidity
- "PILL-ROLLING" tremor
35
What is the treatment for Parkinson Disease?
- -L-dopa to replace dopamine
- -Tx doesn't reverse the changes or stop progression
- -drug therapy becomes less effective over time
36
What are the molecular genetics that contribute to the autosomal dominant form of Parkinson Disease?
--alpha-synuclein was the first gene mutation discovered and it's a component of the Lewy Body
--mutations of LRRK2 (leucine-rich repeating kinase 2) are a more common cause of autosomal dominant Parkinson Disease
37
What are the molecular genetics of the juvenile autosomal recessive form of Parkinson Disease?
- mutation in the gene for parkin (E3 ubiquitin ligase)
- mitochondrial dysfunction
-PINK1 and parkin combo clear dysfunctional mitochondria via mitophagy
38
What is the morphology of Parkinson Disease?
- pallor of substantia nigra and locus ceruleus
- -loss of pigmented catecholaminergic neurons
- Lewy Bodies: cytoplasmic, eosinophilic inclusions
- -dense core surrounded by a pale halo
- -comprised of alpha-synuclein
39
What is Lewy Body Dementia?
- -Lewy neurites contain alpha-synuclein aggregates
- -depigmentation of substantia nigra, locus ceruleus
- -Lewy Bodies in cortical locations
- -HALLUCINATIONS, fluctuating course, frontal signs
- -10-15% of Parkinson Disease develop dementia
40
What is Multiple System Atrophy?
--sporadic disorder characterized by cytoplasmic inclusions of alpha-synuclein in oligodendrocytes
- -involves three neuroanatomic systems:
1) striatonigral circuit (Parkinsonism)
2) olivopontocerebellar circuit (ataxia)
3) autonomic nervous system (orthostatic hypotension)
41
What is the most notable gross brain morphology in Huntington Disease?
- ATROPHY OF THE CAUDATE NUCLEUS
- later the putamen atrophies
- frontal lobe atrophy
42
What is Huntington Disease?
- autosomal dominant mvmt disorder w/ dementia
- rapidly progressive leading to death within 15yrs
-repeat CAG expansions during spermatogenesis cause anticipation and earlier onset (juvenile form)
43
What are the symptoms of Huntington Disease?
- jerky, hyperkinetic mvmts
- later ... bradykinesia and rigidity
- sometimes chorea
- -dystonic mvmts involving the whole body
44
What number of CAG repeats is normal?
10-35 normal
40-50 adult onset
>60 juvenile onset
27-35 normal, but children may develop disease
45
What is the pathogenesis of Huntington Disease?
- degeneration of medium spiny striatal neurons that normally dampen motor activity
- expansions produce a toxic GAIN OF FUNCTION on huntingtin (protein aggregates to form intranuclear inclusion)
46
What is Friedreich Ataxia?
-autosomal recessive spinocerebellar degeneration caused by GAA repeat on 9q13 coding for frataxin
47
What are the symptoms of Friedreich Ataxia?
- gait ataxia by age 10; wheelchair by 5yrs after onset
- clumsy hands
- dysarthria
- depressed DTR's (except extensor plantar reflex)
- joint position and vibratory sense impaired
- CARDIAC arrhythmias and CHF
- 10% have DM
48
What is the common cause of death in patients with Friedreich Ataxia?
- intercurrent pulmonary infections
| - cardiac disease
49
What is Ataxia-Telangectasia?
- autosomal recessive spinocerebellar degeneration that begins in childhood d/t mutated ATM gene on 11q22 that encodes a kinase which normally orchestrates the cell's response to breaks in dsDNA
- increased sensitivity to X-ray-induced chromosome abnormalities; failure to remove cells w/ DNA damage
50
What are the symptoms of Ataxia-Telangectasia?
- telangectasias in CNS, CONJUNCTIVA, face/neck, arms
- development of lymphoid neoplasms (mostly T-cell leukemias), gliomas, and carcinomas
- immunodeficiency and recurrent sinopulmonary infections
- death by early teens
51
What is Amyotrophic Lateral Sclerosis?
- loss of lower motor neurons in the spinal cord and brainstem that project into the corticospinal tracts
- loss of upper motor neurons in the cerebral cortex
52
What are the characteristics of ALS?
- slight male predominance
- onset in 40's or later
- familial form (5-10%) is autosomal dominant
- mutation in superoxide dismutase on chromosome 21
- -gain of function (ala-val substitution is most common)
53
What can be seen on gross morphology of ALS?
-thin anterior roots of the spinal cord d/t loss of anterior horn neurons
- atrophic precentral gyrus
- skeletal muscles w/ neurogenic atrophy
54
What features of neurons in ALS can be seen under microscope?
-neurons contain PAS+ cytoplasmic inclusions called Bunina Bodies, which are remnants of autophagic vacuoles
55
What are the symptoms of ALS?
early: asymmetric hand weakness, DROPPING OBJECTS, difficultly w/ fine motor tasks, arm/leg CRAMPING/spasticity
- muscle atrophy as dz progresses
- fasciculations
- respiratory infections d/t resp. muscle involvement
56
What is the prognosis of ALS?
-50% mortality within 2yrs
57
What is Progressive Bulbar Palsy (Bulbar ALS)?
- degeneration of lower brainstem cranial motor nuclei
- occurs early, progresses rapidly
- deglutination
- phonation difficulties
58
What are the major characteristics of neuronal storage diseases?
- mostly autosomal recessive
- defects in catabolism (sphingolipids, mucolipids, etc.)
- accumulation of enzyme substrates
- neuron death
- cortical involvement, loss of cognitive fxn, seizures
59
What are the characteristics of leukodystrophies?
- mostly autosomal recessive
- -except adrenoleukodystrophy is X-linked
- myelin abnormalities
- lack neuronal storage defects
60
What are the symptoms of leukodystrophies?
- diffuse involvement of white matter
- -motor skills deteriorate
- -spasticity
- -hypotonia or ataxia
61
What are mitochondrial encephalopathies?
- oxidative phosphorylation disorders
- mutations in the mitochondrial genome
- involved GREY MATTER and SKELETAL MUSCLE
62
What are the characteristics of Tay-Sachs?
- HEXA gene for hexosaminidase A (chromosome 15)
- buildup of GM2 gangliosides
- death by age 3
63
What are the symptoms of Tay-Sachs?
- motor incoordination
- muscular flaccidity
- blindness
- cherry red spot in macula of eye
- -normal choroid against swollen retinal ganglion cells
64
What are the two tissues most affected by mitochondrial encephalopathies?
1) muscle
| 2) CNS
65
What is Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)?
--mutation (most commonly) in mitochondrial tRNA-leucine (MTTL1)
--most common neurologic syndrome caused by mitochondrial abnormalities
66
What are the symptoms of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)?
- -recurrent episodes of acute neurologic dysfunction
- -cognitive changes
- -muscle weakness and lactic acidosis
--stroke-like episodes w/ reversible deficits that do NOT correspond to specific vascular territories
67
What is Myoclonic Epilepsy and Ragged Red Fibers (MERRF)?
--maternally-transmitted disease associated w/ mutations in tRNA's other than those in MELAS
- -Symptoms:
- myoclonus
- seizures
- myopathy (w/ ragged red fibers on biopsy),
- ataxia d/t cerebellar neuron loss
68
What is Kearn-Sayre Syndrome ("Ophthalmoplegia Plus")?
-sporadic disorder associated w/ large mitochondrial DNA deletion or rearrangement
69
What are the symptoms of Kearn-Sayre Syndrome?
- cerebellar ATAXIA
- ophthalmoplegia (paralysis of extraocular muscles)
- progressive inability to move eyes and eyebrows
- PIGMENTARY RETINOPATHY
- CARDIAC CONDUCTION DEFICITS
70
What is seen on histology of Kearn-Sayre Syndrome?
- spongiform change in grey and white matter
| - cerebellar neuronal loss
71
What is Leigh Syndrome (Subacute Necrotizing Encephalopathy)?
- disease of infancy associated w/ mutations of nuclear and mitochondrial DNA that involve components of oxidative phosphorylation complexes
- death by age 2
72
What the symptoms of Leigh Syndrome?
- lactic acidemia
- psychomotor development arrest
- feeding problems
- SEIZURES
- extraocular palsies
- weakness w/ HYPOTONIA
73
What is the histology of Leigh Syndrome?
-multifocal regions of symmetric brain tissue destruction w/ spongiform appearance and vascular proliferation
- periventricular midbrain grey matter
- periventricular regions of thalamus and hypothalamus
- tegmentum of pons
