Neuro 2 - degeneration Flashcards
when does brain atrophy occur
- aging
- chronic disease (metabolic, nutritional, ischemia, inherited, inflammatory, idiopathic)
neuronal injuries or response
- cytoplasmic vacuolation
- cytoplasmic inclusion
- reaction of neuronal cell body to axonal damage
- neuroaxonal dystrophy
- cell death (necrosis v apoptosis)
selective neuronal necrosis
- due to high metabolic rate, only specialized neurons are affected
- minimal or no gross changes
pan-necrosis
- malacic disease (malacia = softening)
- general insults may affect all tissue elements (neurons, glia, vessels)
- selective vulnerability (general insults may directly or indirectly destroy neurons and supporting cells/tissue in specific areas of the brain) –> focal or regional malacia
global brain insult that gives rise to focal lesions in brain regions
selective vulnerability
causes of neuronal degeneration (7)
- hypoxia/ischemia
- inflammatory mediators
- bacterial toxins
- heavy metals
- nutritional deficiency (thiamine, copper, vit E)
- reduced ATP generation
- excitotoxicity
reduced ATP generation and neuronal degeneration
- hypoglycemia
- interference with cytochrome oxidase (cyanide poisoning - plants)
- inhibition of oxygen intake (CO poisoning)
- inhibition of kreb’s cycle (fluoroacetate poisoning)
excitotoxicity and neuronal degeneration
- unique form of neuronal cell death
- neurons stimulate themselves to death
- typically due to excess glutamate
- intracellular rise in Ca
consequences of degenerative disease (3)
- increased ICP
- necrosis or apoptosis of nerve tissue
- brain atrophy (if animal survives –> chronic)
gross features of degenerative disease (4)
- brain swelling
- flattening of gyri
- herniation
- asymmetry
origin of degenerative disease in the nervous system (4)
- nutritional disease
- metabolic disease
- toxic disease
- hereditary/familiar/idiopathic (less emphasis)
nutritional causes of degenerative disease (3)
- Cu deficiency
- thiamine deficiency
- vitamin E deficiency
what does copper deficiency cause
swaysback and enzootic ataxia of lamb and goats (degenerative disease)
what does thiamine deficiency cause
-polioencephalomalacia (cortex necrosis)
-chastek’s paralysis
(degenerative disease)
what does vitamin E deficiency cause
equine degenerative myeloencephalopathy (degenerative disease)
metabolic causes of degenerative disease (3)
- hypoglycemia
- aminoacidopathies (bovine)
- hepatic encephalopathy (very important disease)
heavy metals and degenerative disease
arsenic, lead**, mercury
organic/inorganic compounds and degenerative disease
- organophosphates
- cyanide, nitrate/nitrite, fluroacetate, CO
- sodium chloride
- selenium**
toxic plants and degenerative disease
- plant induced storage diseases
- centaurea solstitalis, c repens
microbial toxins and degenerative disease
- focal symmetric encephalomalacia
- tetanus, botulism
- tremogenic toxins
- leukoencephalomalacia (moldy corn poisoning)
2 categories of hereditary/familiar/idiopathic degenerative disease
- storage diseases (inherited v acquired)
- multisystem neuronal degenerations
5 multisystem neuronal degenerations
- primary cerebellar degeneration
- mitochondrial encephalopathy
- motor neuron disease
- neuroaxonal dystrophy
- degenerative leukomyelopathy
what is hypoglycemia
primary energy failure in which highly susceptible cell populations are first affected (selective neuronal necrosis) by delayed onset degeneration and necrosis
what neurons are most susceptible to hypoglycemia
neurons in superficial cerebral cortex and hippocampus (selective neuronal vulnerability)
changes seen in hypoglycemia
- first morphologic evidence is mitochondrial swelling
- light microscopic changes characterized by hypereosinophilia of neurons
causes of hypoglycemia
- insulinoma
- piglets in first week of life (incapable of gluconeogenesis)
2 types of bovine aminoacidopathies
- maple syrup urine disease
- citrullinemia
maple syrup urine disease
- bovine aminoacidopathy
- inherited defect of chain ketoacid dehydrogenase complex enzyme
- accumulation of ketoacids and abnormal metabolites
- marked status spongiosus
citrullinemia
- bovine aminoacidopathy
- inborn error of metabolism of urea cycle
- accumulation of citrulline and ammonia in fluids and abnormal metabolites (hyperammonemia)
- brain edema (cytotoxic edema)
what is hepatoencephalopathy
-CNS disease caused by insufficient processing of portal blood by liver –> caused by portal-caval shunt or extreme hepatic malfunction
mechamisms of cerebral malfunction in hepatoencephalopathy
- inhibition of energy metabolism (loss of kreb’s cycle intermediates)
- direct toxic effects of increased blood ammonia (vasogenic and cytotoxic edema)
- exposure to neurotransmitters (glutamine, GABA) and false neurotransmitters
structural changes in hepatoencephalopathy
- small animals: indistinguishable from normal aging (sometimes primary demyelination that follows prolonged edema)
- herbivores: more subtle changes (astrocyte hypertrophy and hyperplasia)
what is equine degenerative myeloencephalopathy
- neuroaxonal dystrophy affecting proprioceptive system neurons manifesting as spinal cord disease
- functional defect involves axoplasmic transport
what causes equine degenerative myeloencephalopathy
- acquired: vitamin E deficiency (standardbreds, zebra)
- heritable: morgans, rottweilers
anatomic changes in equine degenerative myeloencephalopathy
- axonal spheroids affecting distal axon segment
- spheroids contain neurofilament tangles, membranous whorls, lysosomal bodies
- proprioceptive nuclei of brainstem, brain stem nuclei (level of obex)
- myelin degeneration secondary to axonal degeneration
what is a spheroid
degenerating axon (swollen)
what is thiamine (b1) deficiency
- thiamine is cofactor in oxidative energy pathways
- deficiency results in degenerative and necrotic changes in tissues that have high demand for the vitamin and is associated with decreased high-energy phosphate levels
what tissues are most susceptible to thiamine deficiency
CNS tissue
changes seen in thiamine deficiency
- vascular damage, neuronal necrosis progressing to malacia
- changes differ in distribution between species
- decreased CNS tissue content, decreased thiamine-dependent serum enzymes, occurrence of characteristic lesions
5 suggested mechanisms for polioencephalomalacia
- decreased ruminal production of thiamine by rumenal microflora
- feeder cattle (decreased rumen pH)
- animals consuming thiaminase
- decreased thiamine absorption
- excessive sulfide intake
neuronal lesions in polioencephalomalacia
neuronal lesions predominate early (edema of neuropil, prominent small vessels, neuronal necrosis, cerebral swelling +/- herniation, flattening of gyri, pallor, petechia)
classical lesion of polioencephalomalacia
- laminar necrosis (malacia)
- associated with brain swelling, gitter cells begin to accumulate, deep lamina may be involved
- evident grossly as thin line following sulci and gyri - line autofluoresces under UV light (woods lamp)
what happens if animal with polioencephalomalacia survives for several days
separation of lamina may occur
histological features of cortical necrosis
central chromatolysis –> becomes irreversible –> gone
what is chastek’s paralysis
- carnivores require dietary thiamine (ruminants synthesize their own)
- dietary requirements are readily met unless the animal is consuming a foodstuff high in thiaminase (ex: raw fish)
histological changes in chastek’s paralysis
- edema and vascular dilation
- occurs following 2-4wks deficiency)
- hemorrhage, neuronal degeneration, necrosis, malacia (lower part of brain)
what is chronic salt intoxication
-cascade of pathologic changes follow a sudden imbalance between brain osmolality (astrocyte regulated) and plasma osmolality (kidney regulated) in which the brain becomes hyperosmolar relative to plasma
result of chronic salt intoxication
- CNS edema, brain swelling –> impedes circulation –> cerebrocortical laminar edema, neuronal necrosis, malacia
- pigs, ruminants
- pigs: eosinophilic infiltrates in meninges and around cerebral vessels may be seen in early stages
what is focal symmetrical encephalomalacia
- enteric overgrowth of specific pathogenic bacterial species results in the absorption and systemic dissemination of toxins that induce widespread vascular damage
- in the brain, this vasogenic edema, complimented by a cytotoxic component, causes symmetric malacia
microbes and toxins in focal symmetrical encephalomalacia
- clostridium perfringens D (epsilon toxin) –> pulpy kidney
- e coli (shiga toxin 2e) –> edema disease of swine
sequence of events in focal symmetrical encephalomalacia
- organisms overgrow in intestinal lumen and produce toxins
- systemic dissemination of bacterial toxin results in degeneration of small arterioles (focal hemorrhage and malacia of gray matter, basal ganglia/internal capsule, thalamus, substantia nigra)
lead poisoning
- discarded batteries and lead-based paints are potential sources
- occurs especially in young animals
- calves particularly susceptible
mercury poisoning
- occurs when seed grain treated with alkylmercury compounds is consumed
- swine, cattle most frequently affected
moldy corn poisoning
- widespread multifocal cerebral white matter malacia (leukoencephalomalacia) develops acutely following the prolonged ingestion of fumonisi B1 (fusarium fungus)
- horses particularly sensitive
- malacia secondary to pronounced vasogenic edema
- vascular damage results in hemorrhage (periphery of malacic foci)
lysosomal storage diseases are specific lysosomal hydrolase deficiencies characterized by intralysosomal accumulation of what (5)
- sphingolipids
- glycolipids
- oligosaccharides
- mucopolysaccharides
- autofluorescent lipopogments (neuronal ceroid lipofuscinoses)
acquired lysosomal storage diseases
- plant poisoning
- amphophilic drogue
a-mannosidosis
- naturally acquired storage disease in grazing livestock
- induced by alkaloid swainsonine
- locoweed species (astragalus, ocytropis, swainsona)
mechanism of action of swainsonine
inhibition of the lysosomal a-mannosidase and golgi a-mannosidase II
histo of storage disease
acquired sphingolipids: lamellar membrane-bound concentric bodies
what are transmissible spongiform encephalopathies
- accumulation, typically in CNS, of aberrant isoform of the host encoded normal prion protein (PrPc), designated PrPres, suggested to be infectious by itself and resistant to proteolysis
- vacuolization of gray matter
examples of TSEs
- scrapie
- transmissible mink encephalopathy
- CWD
- bovine spongiform encephalopathy
scrapie genetic sensitivity resistance
- codon polymorphism confers resistance or sensitivity to scrapie
- resistant sheep did not develop disease but are asymptomatic carriers
