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169 Cards in this Set
- Front
- Back
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What determines progression of demyelinating diseases
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capacity of CNS to regenerate normal myelin and degree of secondary damage to axons
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Multiple sclerosis (MS)
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autoimmune demyelinating disorder characterized by distinct episodes of neurologic deficits, separated in time, attributable to white matter lesions that are separated in space; most common demyelinating (1 per 1000 in US)
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when do symptoms of MS start
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onset in childhood or after 50 rare
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clinical course of MS
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relapsing and remitting episodes of variable duration marked by nerological deficits, followed by gradual, partial recovery of neuro fxn
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what is immune response in MS directed against
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components of myelin sheath
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How do SNPs in IL-2 and IL-7 (within DR2 extended haplotype) increase likelyhood of MS
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these cytokine receptor polymorphisms may influence balance btwn pathogenic effector T cells and protective regulatory T cells
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T cells in MS hypothesis
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initiated by CD4+ Th1 and Th17 T cells that react against self myelin antigens and secrete cytokines
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what secretes IFN-gamma and activates macrophages in MS
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Th1 cells
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what promotes recruitment of leukocytes in MS
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Th17 cells
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what causes humoral immunity to be suspected to have a role in MS
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early observation of oligoclonal bands of IgG in CSF; B-cell depletion can decrease incidence of demyelinating lesions
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lesion appearance in MS
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multiple, well-circumscribed, somewhat depressed, glassy, gray-tan, irregularly shaped plaques
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locations of lesions in MS
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throughout white matter and can extend into gray matter-commonly adjacent lateral ventricles; often centered on small veins; frequent in optic nerves and chiasm, brainstem, ascending and descending fiber tracts, cerebellum, and spinal cord
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microscopic active plaque in MS
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abundant macrophages containing PAS-pos debris; inflammatory cells; relative preservation of axons and depletion on oligodendrocytes
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microscopic inactive plaque in MS
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little/no myelin found, reduction in # of oligodendrocyte nuclei; axons greatly diminished in #
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4 basic patterns of active plaques in MS
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1&2) sharply demarcated and centered on blood vessels with or without deposistion of immunoglobulin and complement 3&4) less well demarcated and are not centered on blood vessels with widespread or central only apotosis of oligodendrocytes
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shadow plaques of MS
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border btwn normal and affected white matter not sharply circumscribed
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what are shadow plaques interpereted as
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evidence of partial and incomplete remyelination by surviving oligodendrocytes
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optic neuritis and retrobulbar neuritis and MS
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often 1st manifestation, although only 10-50% with optic neuritis go on to dvlp MS
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neuromyelitis optica or Devic deisease
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svlp of synchromous or near-synchronous bilateral optic neuroitis and spinal cord demyelinnation
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neuromyelitis optica or Devic deisease cause
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humoral immune mechanisms-necrosis in damaged areas of white matter and vascular deposition of immunoglobulin and complement; antibodies to aquaporins in many individuals
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aquaporin important fxn
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maintenance of astrocytic foot process (thus integrity of blood-brain barrier)
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acute disseminated encephalomyelitis (ADEM)
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diffuse, monophasic demyelinating disease that follows either viral infection or rarely viral immunization
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ADEM symptoms and progression
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headache, lethargy, and coma; rapid-up to 20% die, rest recover completely
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acute necrotizing hmorrhagic encephalomyelitis (ANHE)
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fulminant syndrome of CNS demyelination usually in young adults and children; preceded by recent URI; fatal, with significant defects in most survivors
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ADEM morphology
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grayish discoloration around white-matter vessels; myelin loss with relative preservation of axons
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ADEM vs MS
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findings aren't as focal as in MS; all lesions appear similar (monophasic)
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ANHE morphology
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perivenular distribution of demyelination and widespread dissemination throughout CNS, more severe lesions than ADEM and include destruction of small blood vessels, disseminated necrosis of white and gray matter with acute hemorrhage, fibrin deposition, and abundant neutrophils
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ADEM and ANHE causes
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ADEM=may represent an acute autoimmune rxn to myelin; ANHE=may represent a hyperacute variant
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central pontine myelinolysis
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loss of myelin in a roughly symmetric pattern invloving basis pontis and portions of the pontine tegmentum but sparing periventricular and subpial region
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what is central pontine myelinolysis most commonly associated with
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rapid correction of hyponatremia, other electrolyte/osmolar imbalances, orthotopic liver transplantation
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common theme among neurodegenerative disorders
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presence of protein aggregates that are resistant to degradation through ubiquitin-proteasome system
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2 approaches to degenerative diseases
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sympathomatic/anatomic and pathologuc
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Alzheimer disease (AD) morphology of brain
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variable cortical atrophy with widening of sulci-most pronounced in frontal, temporal, and parietal lobes; compensatory ventricular enlargement secondary to loss of parenchyma and reduced brain volume
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what brain structures are involved early in the course of Alzheimer's
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medial temporal lobe-including hippocampus, entorhinal cortex and amygdala
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major histological abnormalities of AD
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neuritic (senile) plaques and neurofibrillary tangles
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neuritic plaques
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focal, spherical collections of dilated, tortuous, neuritic processes often around a central amyloid core, which may be surrounded by a clear halo
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amyloid core
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contains several abnormal proteins, with the dominant component AB; others are complement proteins, pro-inflammatory cytokines, a1-antichymotrypsin, and apolipoproteins
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diffuse plaques
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represent early stage plaque dvlp in AD; deposition of AB with staining characteristics of amyloid in absence of surrounding neuritic rxn
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neurofibrillary tangles
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bundles of filaments in cytoplasm of neurons that displace or encircle the nucleus; basophilic in H&E
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where are neurofibrillary tangles commonly found
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cortical neurons, especially in entorhinal cortex as well as pyramidal cells of hippocampus, amygdala, basal forebrain, and raphe nuclei
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what makes up filaments in neurofibrillary tangles
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protein tau, MAP2, ubiquitin
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tau
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axonal microtubule-associated protein that enhances mictotubule assembly
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other pathologic findings of AD
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Cerebral amyloid antiopathy (CAA), granulovaculolar degeneration, Hirano bodies
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fundamental abnormality in AD
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deposition of AB peptides, derived via processing of APP
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APP
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cell surface protein with single transmembrane domain; gene is on chromosome 21
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ApoE isoform
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promotes AB generation and deposition; ~1/4 risk of developing AD sporadically
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what occurs to tau with dvlp of tangles in AD
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shifts to somatic-dendritic distribution, becomes hypophosphoylated, and loses ability to bind to microtubules
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what does a mutation in tau gene cause (MAPT)
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frontotemporal dementia-no AB deposition nor AD
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biochemical markers associated with dementia
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loss of choline acetyltransferase, synaptophysin immunoreactivity, and amyloid burden
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frontotemporal dementia (FTD) with parkinsonism
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mutations in tau can cause
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pick disease (lobar atrophy)
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rare, distinct, progressive dementia characterized by early onset of behavorial changes together with alterations in personality and language disturbances; most cases sporadic
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morphology of picks diseae
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pronounced, frequently asymmetric, atrophy of frontal and temporal lobes with sparing of posterior 2/3 of superior temporal gyrus and rare involvement of parietal/occipital lobes; may be bilateral atrophy of caudate nucleus and putamen
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microscopy of picks
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neuronal loss more severe in outer 3 layers of cortex; surviving neurons have characteristic swelling (pick cells) and others pick bodies
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pick bodies
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cytoplasmic, round to oval, filamentous inclusions that are weakly basophilic but stain strong with silver methods; straight filaments, vesiculated ER, and paired helical filaments similar to AD and contin 3R tau
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progressive supranuclear palsy
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truncal rigidity with dysequilibrium and nuchal dystonia; pseudobulbar palsy and abnormal speech; ocular disturbances (vertical gaze palsy progressing to difficulty with all eye movements); mild progressive dementia; 5-7th decades; fatal 5-7 yrs after onset
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progressive supranuclear palsy morphology
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widespread neuronal loss in globus pallidus, subthalamic nucleus, substantia nigra, colliculi, periaqueductal gray matter, and dentate nucleus of cerebellum; globose neurofibrillary tangles in affected regions in neurons and glia
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corticobasal degeneration
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disease of elderly; extrapyrimidal signs, asymmetric motor disturbances, sensory cortical dysfunction; cognitive decline; MAPT haplotype closely associated
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corticobasal degeneration morphology
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cortical atrophy mainly of motor, premotor, and anterior parietal lobes; these regions show severe neuron loss, gliosis, and 'ballooned' neurons
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what is generally found with FTD without tau pathology
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ubiquitin-containing inclusions in superficial cortical latyers and in dentate gyrus
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parkinsonism
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diminished facial expression, stooped posture, slowness of voluntary movement, festinating gait, rigidity, and pill-rolling tremor; damage to nigrostriatal dopaminergic system
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festinating ait
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progressively shortened, accelerated steps
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principle diseases that involve the nigrostriatal system
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Parkinson's, multiple system atrophy, postencephalitic parkinsonism, and progressive supranuclear palsy and corticobasal degeneration
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parkinson disease diagnosis
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progressive L-DOPA-responsive signs of parkinsonism (tremor, rigidity, and bradykinesia) in absence of toxic or other known cause
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morphology of parkinsons
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pallor of substantia nigra and locus ceruleus; Lewy bodies may be found in remaining neurons
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Lewy bodies
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single/multiple, cytoplasmic, eosinophilic, round to elongated inclusions that often have dense core surrounded by pale halo
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composition of Lewy bodies
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fine filaments, densely packed in core but loose at rim; filaments composed of alpha-synuclein
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alpha-synuclein
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abundant lipid-binding protein normally associated with synapses that is also a major component of Lewy bodies
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parkin mutation
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causes juvenile autosomal recessive PD; E3 ubiquitin ligase with wide range of substrates; Lewy bodies absent in most cases
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dementia with Lewy bodies features
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fluctuating course, hallucinations, prominent frontal signs
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dementia with Lewy bodies with Lewy neurites gross pathology
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depigmentation of substantia nigra and locus ceruleus paired with relative preservation of cortex, hippocampus, and amygdala; evidence of following progression: medulla, midbrain, nervous sytem to reach cortex
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Mutliple System Atrophy (MSA)
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group of disorders characterized by the presence of glial cytoplasmic inclusions, typically within cytoplasm of oligodendrocytes, that can have different patterns of clinical presentation
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MSA-P, MSA-C, and MSA-A
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parkinsonism previously known as striatonigral degeneration; cerebellar dysfunction, previously known as olivopontocerebellar atrophy; autonomic dysfunction previously known as Shy-Drager syndrome
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automomic symptoms of MSA-A cause
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cell loss from catecholaminergic nuclei of medulla and intermediolateral cell column of the spinal cord; usually no gross specific findings
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distinct inclusions in MSA
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contain a-synuclein as well as ubiquitin and aB-crystallin; ultrastructurally distinct with 20-40 nm tubules
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a-synuclein in oligodendrocytes
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perplexing since it is a neuronal protein associated with synaptic vesicles; may be aquired secondarily from injured or dying neurons
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huntinton disease (HD)
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autosomal dominant characterized by progressive movement disorders and dementia, histologically by degeneration of striatal neurons
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movements in HD
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jerky, hyperkinetic, sometimes dystonic movements involving all parts of the body (chorea)
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genetics of HD
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polyglutamine trinucleotide repeat expansion disease on 4p16.3; encodes a protein called huntingtin; CAG repeat:normal 6 to 35 repeats
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when do repeat expansions occur in HD
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during spermatogenesis-paternal transmission is associated with early onset in the next generation (anticipation)
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morphology of HD
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atrophy of the caudate nucleus and putamen, globus pallidus secondarily atrophies; lateral and 3rd ventricles dilated
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microscopy of HD
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severe loss of striatal neurons
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pathologic changes in caudate and putamen in HD occur in what direction
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caudate=medial to lateral and putamen=dorsal to ventral; loss of small neurons first
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two populations of neurons relatively spared in HD
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diaphorase-positive neurons that contain NO synthase and large cholinesterase-pos neurons; serve as local interneurons
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one of most affected neurons in HD and what does this cause
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medium-sized spiny neurons that use GABA (and others); dysregulation of basal ganglia circuitry that modulates motor output-usually fxn to dampen motor activity
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spinocerebellar ataxias
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characterized by neuronal loss from affected areas and secondary degeneration of white-matter tracts; 29 distinct diseases/entities currently
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3 types of mutations recognized in spinocerebellar ataxias
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1) polyglutamine diseases linked to expansion of CAG repeat 2) expansion non-encoding region repeats (similar to myotonic dystrophy) 3) and other types of mutations
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Friedreich ataxia
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distinctive spinocerebellar degeneration; autosomal recessive progressive illness; begins in 1st decade with gait ataxia followed by hand clumsiness and dysarthria
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impairments in friedreich ataxia
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DTR depressed/absent, extensor plantar reflex present; joint position and vib sense impaired, sometimes loss of pain and temp sesation and light touch; most dvlp pes cavus and kyphoscoliosis; high incidence of cardiac arrhythmias and CHF; concomitant diabetes in 10%
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cause of friedreich ataxia
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expansion of GAA trinucleotide-repeat that encodes frataxin resulting in low levels of the protein; causes features of other SCAs along with generalized mitochondrial dysfunction)
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frataxin
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normally localizes to inner mitochondrial membrane where it may have a role in regulating iron levels
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morphology of friedreich ataxia
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spinal cord shows loss of axons and gliosis in posterior columns, distal portions of corticospinal tracts, and spinocerebellar tracts; heart enlarged and may have pericardal adhesions (inflammation and fibrosis in 50%)
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degeneration of what neurons occurs in friedreich ataxia
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spinal cord (Clarke column), brainstem (CN nuclei VIII, X, and XII), cerebellum (dentate and purkinje cells of superior vermis), and Betz cells of motor cortex; large dorsal root ganglia neurons decreased in number
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Ataxia-Telangiectasia
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autosomal recessive cahracterized by ataxic-dyskinetic syndrome beginning in early childhood, with subsequent dvlp telangiectasias in conjunctiva and skin; immunodeficiency
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ataxia-Telangiectasia mutated gene (ATM)
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encodes kinase with critical role in orchestrating cellular response to dsDNA breaks
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Ataxia-Telangiectasia morphology
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predominately in cerebellum with loss of purkinje and granule cells; also degeneration in dorsal columns, spinocerebellar tracts, and anterior horn cells, and a peripheral neuropathy
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amphicytes
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bizarre enlargement of nucleus to 2-5 times normal size; occur in many locations with ATM
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clinical manifestations of UMN loss
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paresis, hyperreflexia, spasticity, and extensor plantar responses (Babinski sign)
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clinical manifestations of LMN loss
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muscular atrophy, weakness, fasiculation
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Amytrophic Lateral Sclerosis (ALS)
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loss of motor neurons in spinal cord and brainstem that project in corticospinal tracts; manifests in 5th decade or later; 5-10% familial with autosomal dominance
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1/4 of familial ALS is caused by
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mutations in gene encoding copper-zinc superoxide dismutase (SOD1) on chromosome 21; gain of fxn mutant; rapid course and rarely has UMN signs
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dynactin
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protein involved in retrograde axonal transport
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VAMP-associated protein B
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regulation of vesicle transport
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alsin
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contains guanine nucleotide exchange factor domains and associated with regulation of endosomal trafficking through interaction with Rab5b
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morphology of ALS
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anterior roots of spinal cord are thin; precentral gyrus may be atrophic in severe cases
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microscopic ALS
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reduction in # of anterior-horn neurons with associated reactive gliosis and loss of anterior-root myelinated fibers (also in hypoglossal, ambiguous, and motor trigeminal CN nuclei)
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Bunina bodies
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PAS-positive cytoplasmic inclusions in neurons; appear to be remnants of autophagic vacuoles
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what causes myelin loss in ALS
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degeneration of neurons
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clinical features of ALS
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early: aymmetric weakness of hands (dropping objects and difficulty performing fine motor tasks), cramping and apsticity of arms and legs; later: muscle strength and bulk diminish and fasiculations occur; late: respiratory muscle involvement
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bulbospinal atrophy (Kennedy syndrome)
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x-linked adult onset cahracterized by distal limb amyotrophy and bulbar signs like atrophy and fasciculations of tongue and dysphagia
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manifestations of bulbospinal atrophy
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androgen insensitivity, gynecomastia, testicular atrophy, and oligospermia
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microscopic bulbospinal atrophy
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degeneration of LMNs in spinal cord and brainstem
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gene defect in bulbospinal atrophy
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expansion of CAG/polyglutamine repeat in androgen receptor; nuclear inclusions containing aggregated androgen receptor can be found
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spinal muscular atrophy
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mainly affects LMNs in children; selective loss of anterior-horn cells and atrophy of anterior spinal roots
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neuronal storage diseases
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mostly autosomal recessive caused by deficiency of a specific enzyme in catabolism of spingolipids, mucopolysaccarides, or mucolipids
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leukodystrophies
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myelin abnormalities (synthesis or turnover) and generally lack neuronal storage defects; diffuse involvement of white matter leads to deterioration in motor skills, spasticity, hypotonia, or ataxia
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mitochondrial encephalomyopathies
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group of disorders of oxidative phosphorylation; typically involve gray matter as well as skeletal muscle
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neuronal ceroid lipofuscinoses (NCL)
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set of inherited lysosomal storage diseases grouped due to lipofuscin accumulation in neurons
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what does neuronal dysfunction in neuronal ceroid lipofuscinoses lead to
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combination of blindness, mental and motor deterioration, and seizures
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CLN1
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common cause of infintile NCL; encodes palmitoyl protein thioesterase 1 (PPT1) which removes pamitate residues from proteins
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CLN3
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most cases of juvenile NCL (aka Batten disease); encodes palmitoyl-protein-9 desaturase: related to regulation of membrane-associated palmitoylated proteins
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Tay-sachs disease
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begins in early infancy with dvlp delay, followed by paralysis and loss of neurologic fxn, and death after several years
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Krabbe disease
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leukodystrophy; autosomal recessive; deficiency of galactocerebroside B-galactosidase (required for metabolism to galactase); disease caused by alternate catabolism pathway that generates galactosylsphingosine
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progression of Krabbe disease
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rapid; onset 3-6 months, survival past 2 uncommon; motor signs (stiffness and weakness), gradual worsening in feeding difficulties
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brain in Krabbe disease
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loss of myelin and oligodendrocytes in CNS and similar process for PNS; neurons and axons relatively spared
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unique and diagnostic feature of Krabbe disease
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aggregation of engorged macrophages (globoid cells) in parenchyma and around blood vessels
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metachromatic leukodystrophy
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autosomal recessive; deficiency of lysosomal enzyme arylsulfatase A; leads to myelin breakdown (unknown MOA)
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arylsulfatase A
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present in variety of tissues; cleaves sulfate from sulfate-containing lipids, which is the first step in their degradation
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metachromatic leukodystrophy microscopy
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macrophages with vacuolated cytoplasm scattered throughout white matter; membrane-bound vacuoles contain complex crystalloid structures composed of sulfatides
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metachromasia
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when bound to certain dyes such as toluidine blue, sulfatides shift the absorbance spectrum of the dye
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diagnosis of metachromatic leukodystrophy
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metachromasia; detection of metachromatic material in urine
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adrenleikosystrophy
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several distinct forms; progressive sidease with symptoms referable to myelin loss of CNS and Peripheral nerves as well as adrenal insufficiency; inability to metabolize very-long-chain-fatty acids (VLCFAs) within peroxisomes
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mutations associated with adrenleikosystrophy
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ALD gene-encodes member of ATP-binding cassette transporter damily of proteins (ABCD1)
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pelizaeus-Merzbacher disease
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x-linked, invariably fatal leukodystrophy beginning early childhood/after birth; slowly progressive due to white matter dysfxn
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presentation of pelizaeus-Merzbacher disease
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pendular eye movements, hypotonia, choreoathetosis, and pyramidal signs early in disease followed by spasticity, dementia, and ataxia
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mutations associated with pelizaeus-Merzbacher disease
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proteolipid protein (PLP) and DM20; unknown MOA
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Canavan Disease
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megalocephaly, severe mental deficits, blindness, and signs/symptoms of white matter injury beginning in early infancy and relentlessly progressing to death within few years of onset
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morphology of canavan disease
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spongy degeneration of white matter; accumulation of N-acetylaspartic acid as consequence of LOF mutation in deacetylating enzyme aspartoacylase
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Alexander disease
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megalencephaly, seizures, and progressive psychomotor retardation; white-matter loss (frontal to occipital gradient); accumulation of Rosenthal fibers around blood vessels in subpial and subependymal zones and in brain parenchyma
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suspected cause of alexander disease
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dominant GOF mutations associated with decreased capacity to form filaments as well as induction of stress responses
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Vanishing-White-Matter leukodystrophy
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mutations in genes encoding any of 5 subunits of eukaryotic initiation factor 2B (eIF2B); begins early life with ataxia and seizures common, survive few years after onset
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Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
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most common neurologic syndrome caused by mitochondrial abnormalities; recurrent episodes of acute neurologic dysfunction, cognitive changes, and evidence of muscle involvement with weakness and lactic acidosis
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stroke-like episodes of MELAS
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associated with reversible deficits that so not correspond well to specific vascular territories
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most prevalent mutations associated with MELAS
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tRNAs
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myoclonic epilepsy and ragged red fibers (MERRF)
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maternal transmission; myoclonus, a seizure disorder, and evidence of myopathy; ataxia common; mutations in tRNA distinct from MELAS
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Leigh Syndrome (subacture necrotizing encephalopathy)
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early childhood characterized by lactic acidemia, arrest of psycomotor dvlp, feeding problems, siezures, extra-ocular palsies, and weakness with hypotonia; death within 1-2 yrs
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histo of Leigh syndrome
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multifocal, moderately symmetric regions of destruction of brain tissue with spongiform appearance and proliferation of blood vessels
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most common affected areas in Leigh syndrome
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periventricular gray matter of midbrain, tegmentum of pons, periventricular regions of thalamus and hypothalamus
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mutations assocaited with Leigh syndrome
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nucleat and mitochondrial mutations
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heteroplasmy
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unequal distribution of mitochondrial DNA
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Kearn-Sayre syndrome
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sporadic disorder most often associated with large mitochondrial DNA deletion/rearrangement; cerebellar ataxia, progressive external opthalmoplegia, pigmentary retinopathy, and cardiac conduction defects
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path of Kearn-Sayre syndrome
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spongiform change in gray and white matter, with neuronal loss most evident in cerebellum
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alpers disease
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neurologic symptoms with evidence of hepatic dysfunction and path findings of hepatitis and bile duct proliferation; within fist few yrs of life with severe intractable seizures followed by dvlp delay, hypotonia, ataxia, and cortical blindness
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neuronal loss in alpers
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cerebral cortex and throughout deeper structures, and spongiform degeneration of gray matter
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mutations associated with alpers
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nuclear gene encoding DNA polymerase gamma-responsible for replication of mitochondrial genome
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Thiamine (vit B1) deficiency
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beriberi; associated with cardiac failure; psychotic symptoms or ophthamoplegia that begin abruptly (Wernicke encephalopathy); Korsakoff syndrome (memory disturbances and confabulation)
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Wernicke encephalopathy morphology
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foci of hemorrhage and necrosis in mamilary bodies and walls of 3rd and 4th ventricles
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what lesions correlate with memory disturbance and confabulation of Korsakoff
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dorsomedial nucleus of thalamus
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Vit B12 deficiency
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anemia and neurologic symptoms; numbness, tingling, and slight ataxia in lower extremities; may progress rapidly to include spastic weakness of lower extremities
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microscopy of B12 deficiency
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swelling of myelin layers producing vacuoles; begins segmentally at midthoracic level of spinal cord; over time axons in ascending tracts of posterior columns and descending pyramidal tracts degenerate (subsacute combined degeneration of the spinal cord)
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hypoglycemia and CNS
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resembles oxygen deprivation; initially selective injury to large pyrimidal neurons of cerebral cortex; hippocampus also vulnerable; purkinje cells of cerebellum
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pyrimidal neurons of cerebral cortex with severe hypoglycemia
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pseudolaminar necrosis of cortex, predominately involving deep layers
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hyperglycemia and CNS
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associated with ketoacidosis or hyperosmolar coma; dehydrated and dvlps confusion, stupor, and eventually coma
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why must fluid depletion be corrected slowly in hyperglycemia
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otherwise severe cerebral edema may follow
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hepatic encephalopathy and CNS
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predominantly glial
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Carbon monoxide and CNS
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hypoxia resulting in selective injury of neurons of layers III and V of cerebral cortex, sommer sector of hippocampus, purkinje cells; demyelination of white matter tracts may be a latter event
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methanol and CNS
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preferentially affects retina-degeneration of retinal ganglion cells may cause blindness; selective bilateral putamenal necrosis and focal white-matter necrosis when exposure severe
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ethanol and CNS
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cerebellar dysfxn in chronic alcoholics (truncal ataxia, unsteady gait, nystagmus); atrophy and loss of graule cells mostly in anterior vermis
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bergmann gliosis
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loss of purkinje cells and proliferation of adjacent astrocytes btwn depleted granular cell layer and molecular layer of cerebellum
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radiation and CNS
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delayed effects=rapidly evolving symtpoms including headaches, nausea, vomiting, and pailledema months/years after; coagulative necrosis and edema usually in white matter
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