Chapter 15 - Neurological Disorders Flashcards
a mass of cells whose growth is uncontrolled and that serves no useful function
Tumor
a cancerous tumor; lacks distinct border and may metastasize. (If you cut into it, it’s gone.)
Malignant tumor
a noncancerous tumor; has a distinct border and cannot metastasize.
Benign tumor
a process by which cells break off of a tumor, travel through the vascular system, and grow elsewhere in the body.
Metastasis.
a cancerous brain tumor composed of one of several types of glial cells.
Glioma
contain initiating cells which originate from transformations of neural stem cells. Rapidly proliferate and give rise to glioma
Malignant gliomas
a benign brain tumor composed of the cells that constitude the meninges.
Meningioma
Tumors can damage brain tissues by 2 means
Compression; Directly or indirectly (blocking flow of CSF, hydrocephalus
Infiltration: more difficult to treat, hard to remove tumor once it’s infiltrated neurons and tissue.
Primary symptom is seizures. Overabundance of electrical activity in a vessel, weakening the vessel. Causes electrical activity in the brain - causing seizures
Epilepsy
Often preceded by an aura, such as a smell, hallucination or feeling.
Seizure
strong smell - somatosensory cortex.
feelings of depression - temporal lobe
Seizure that does not involve the whole brain. Has a definite source of focus/irritation. Can be removed and number of seizures can be diminished. (most common form)
2 types.
Partial seizures
Involves entire brain. Starts at one hemisphere, crosses the corpus collosum to get to the opposite hemisphere.
Generalized epilepsy
Type of seizure.
symptoms are primarily sensory, motor or both. Symptoms spread as epileptic discharge spreads. Not associated with loss of consciousness.
Simple partial seizure
Type of seizure
Often restricted to the temporal loves (temporal lobe epilepsy). Patient engages in compulsive and repetitive simple behaviors (automatisms). Leads to loss of consciousness. (Most common type)
Complex partial seizure
Patient engages in compulsive and repetitive simple behaviours.
Automatisms
Type of seizure.
Tonic-clonic convulsions. Rigidity (tonus) ~ 15 s. All muscles contract, arms are rididly outstretched.
Tremors (clonus) ~ 30s. Muscles begin trembling, jerking, quick at first but slows down, eyes rolld, face in contorted, sweating, salivation.
firing begings at focus spreads to other regions by corpus callosum.
Resulting hypoxia may cause brain damage.
Grand mal seizure (type of generalized seizure)
Type of seizure.
More common in children. Not associated with convulsions.
A disruption of consciousness associated with a cessation of ongoing behaviour. Unresponsive, usually do not notice attacks.
can occur several hundred times a day.
Absence (petite mal)
50% of patients with seizures show damage to the ____
Hippocampus
a condition in which a patient undergoes a series of seizures withouht regaining consciouness. May cause significant hippocampal damage.
Caused by excessive release of glutamate during seizure.
Status epilepticus
type of seizure where infant gets a very high fever; does not lead to epilepsy
Febrile seizures
Seizure - when sudden release of the inhibiting effects of alcohol or barbiturate leaves the brain in a hyper-excitable condition (can be fatal)
Caused by alcohol or barbiturate withdrawal.
___ genes assocaited with seizure disorders. (not common cause)
NEarly all genes identified control the production of ion channels.
70
Treatment for seizures
Anticonvulsant drugs (increase effectiveness of inhibitory synapses) Brain surgery (remove region of the brain surronding the focus, usually located in the MTL)
A series of alternating bilateral brain stimulations eventually elicits convulsions.
typicall the amygdala or hippocampus. Neural changes are permanent.
Comparable to the development of epilepsy seen following a head injury
the kindling phenomenon
development of epilepsy
epileptogenesis
third leading cause of death. most common cause of adult disability
stroke
common consequences of stoke
amnesia, aphasia, paralysis, coma
area of dead or dying tissue produced by the stroke
infarct
dysfunctional area surrounding the infarct
Penumbra
goal of treatment following a stroke
save the penumbra.
Two major causes of Cerebrovasular accidents
hemorragic
ischemic
cerebrovasular accident caused by the rupture of a cerebral blood vessel. (malformed blood vessel; weakened blood vessel from high blood pressure)
Blood seeps out and accumulates within the brain, putting pressure on the surrounding tissue.
Hemorrhagic Strokes
pathological balloon-like dilation that forms in the wall of an artery at a point where the elasticity of the artery wall is defective.
- congenital
- vascular posions or infection
- weakened blood vessel from high blood pressure
Aneurysm
cerebrovasular accident caused by occulsion of a blood vessel
Ischemic Stroke
blood clot that forms within a blood vessel, which may occlude it.
thrombus
piece of material that forms in one part of the vascular system, breaks off, carried by blood stream until it reaches a smaller artery.
embolus
interruption of the blood supply to a region of the body.
Ischemia
toxic cells that can destroy nucleus, proteins and fatty acids
Free radicals
protein that helps guide the growth of neurons in developing brain
Neural adhesion protein
Lack of enzyme that converts phenylalanine into tyrosine
XS phenylalanine in blood interferes with myelinization of neurons in CNS
Given food with phenylalanine, accumulates, severe mental retardation
Phenylketonuria (PKU)
Causes brain to swell and damage itself against the inside of the skull and dura mater.
Metabolic “storage” disease.
1 or more enzymes are missing, waste products cannot be destroyed by lysosomes, accumulation.
Lysosomes get larger, cells get larger, brain swells.
Symptoms begin around 4 months.
Exaggerated startle response, listlessness, irritability, spasticity, seizures, dementia, death .
Tay-Sachs disease
Caused by a nondisjunction event. a gamete (a sperm or egg cell) is produced with an extra copy of chromosome 21
Trisomy 21
failure of chromosome pairs to separate properly during cell division
The result of this error is a cell with an imbalance of chromosomes
Nondisjunction
When some of the cells in the body are normal and other cells have trisomy 21
Mosaicism
The long arm of chromosome 21 is attached to another chromosome, often chromosome 14 or itself (called an isochromosome)
Robertsonian translocation
Consequences of down syndrome
Disfigurement Flattened skull and nose Folds of skin over the inner corners of the eyes Short fingers Retarded intellectual development Brain ~ 10% lighter Convolutions (gyri and sulci) are simpler and smaller Frontal lobes are smaller Superior temporal gyrus is thin Often serious medical complications
Contagious brain disease whose degenerative process gives the brain a sponge-like appearance.
Once introduced into the cell the PrPsc can cause the PrPc (normal) to become misfolded.
Transmissible Spongiform Encephalopathies
protein that can exist in two forms that differ only in their 3-D shape.
Prions
Accumulation of misfolded prion protein is responsible for _____
TSE
PrPc (normal) and PrPsc (prion infected)
PrPSC -protease-resistant (prion protein also heat resistant)
Abnormal protein taken up into neuron by retrograde transport
PRION DISEASES
_______ gives the brain a ‘swiss cheese’-like appearance
Encephalopathy
programmed cell death
apoptosis
enzymes generated by the cell initiating cell death
Caspases
NEURODEGENERATIVE DISEASE
Rapidly progressive dementia, memory loss, personality changes and hallucinations
Physical problems such as speech impairment, jerky movements, balance and coordination dysfunction (ataxia), changes in gait, rigid posture, and seizures
Death
Creutzfeldt-Jakob Disease (CJD)
A disease caused by degeneration of the nigrostriatal system – the dopamine-secreting neurons of the substantia nigra (send axons to BG)
Parkinson’s Disease
abnormal circular structures with a dense core consisting of a-synuclein protein (presynaptic protein); found in dopaminergic nigrostriatal neurons of Parkinson’s patients.
Lewy Body
Genetic causes of PD
Gene mutations. Mutation on chromosome 4. Gene that codes for alpha-synuclein (SNCA) – located in presynaptic terminal of DA cells. Toxic gain of function. Dominant. Abnormal SNCA becomes misfolded, forms aggregations - make up lewy bodies.
Mutation on chromosome 6- produces an abnormal Parkin protein. Recessive disorder. Loss of function. Normal Parkin plays a role. Trafficking defective/misfolded proteins to proteasomes for destruction (recycling) Defective Parkin: Allows abnormally high levels of defective proteins to accumulate in dopaminergic neurons. Fails to ubiquinate abnormal proteins. Kills the cell
targets the abnormal proteins for destruction by the proteasomes
Ubiquitination
Why the Nigrostriatal Pathway?
Ca2+ channels – regulate spontaneous activity of DA cells in NGS pathway
Na+ channels – regulate spontaneous activity of DA cells in other pathways Animal models – SNCA, increased Ca2+, increased DA = kill cells DA cells in other pathways don’t contain increased Ca2+, neurons are spared
Treatment for PD
L-DOPA – precursor of DA
what does L-DOPA do?
Increased level of L-DOPA in brain causes remaining DA neurons to secrete more DA, alleviates symptoms. Short-term. Number of nigrostriatal DA neurons decline – symptoms become worse
High levels of L-DOPA produce side effects – acting on DA systems other than nigrostriatal
Hallucinations and delusions
blocks the effects of MPTP in the animal model
Deprenyl (monamine agoinst)
Transplantation of fetal tissue/neural stem cells
Stereotaxic surgery
surgical destruction of the internal division of the globus pallidus
Pallidotomies
Transplantation of fetal tissue
Re-establish the secretion of DA in the neostriatum
Tissue is obtained from the SN of aborted human fetuses and implanted into the caudate nucleus and putamen.
Fetal cells grow in their new host and secrete DA, reducing symptoms (initially).
Develop severe dyskinesias (involuntary movements)
Misfolded SNCA is transferred from the recipient’s own neurons to the grafted neurons.
No longer recommended.
undifferentiated cells with potential to develop into DA neurons.
Implanted neural stem cells in the caudate.
Stem cells differentiated into DA neurons, astrocytes and other cells that protect and repair neurons.
Motor behavior improved.
Transplantation of neural stem cells
GPi - Output of BG
Output, directed through the thalamus to motor cortex, is inhibitory.
Decrease in activity of DA input to caudate nucleus and putamen causes an increase in activity of GPi.
Damage to GPi might relieve the symptoms of PD.
Lesions of subthalamic nucleus
Subthalamic nucleus has an excitatory effect on GPi
Damage to subthalamus decreases the activity of this region and removes some of the inhibition on motor output.
Normal people – damage to subthalamus causes involuntary jerking and twitching.
PD patients – damage to subthalamus causes normal motor activity (normally depressed) .
Stimulation of subthalamus (deep brain stimulation)
Implant electrodes in subthalamic nucleus and attach a device that permits PD patient to electrically stimulate the brain.
Fewer side effects (compared to surgery).
How can stimulation and lesions of the same area produce the same effect???
Production of GAD (gene therapy for PD)
Genetically modified virus into the subthalamic nucleus of PD patients.
Delivered a gene for GAD (enzyme that makes GABA)
Production of GAD turned some of the glutamate neurons into inhibitory, GABA neurons.
Activity of GPi decreased, activity of supplementary motor area increased, symptoms improved.
Degeneration of caudate nucleus and putamen
Huntington’s Disease
Uncontrollable movements, jerky limb movements.
Progressive, cognitive and emotional changes
Death (10-15 years)
Huntington’s Disease
caused by an autosomal dominant mutation in either of an individual’s two copies of a gene called Huntingtin, which means any child of an affected person typically has a 50% chance of inheriting the disease.
Huntington’s Disease
hyperkinetic
Removes inhibitory control of motor areas in cortex
Huntington’s Disease - genetics
Dominant gene on chromosome 4.
Gene that codes the huntingtin protein (htt).
Repeated sequence of bases that code for the amino acid glutamine.
Abnormal htt becomes misfolded and forms aggregates in nucleus.
Cell death: apoptosis.
Normal Huntingtin (htt)
Forms complex with clatherin, Hip1 and AP2.
Involved in endocytosis and neurotransmitter release. Normal htt facilitates the production and transport of brain derived neurotropic factor (BDNF)
Htt protein has abnormally long glutamine tract.
May lead to abnormal endocytosis and secretion of neurotransmitters.
Striatal death by apoptosis.
Caspase-3.
Huntington’s Disease
neurotropic factor critical for the survival of neurons
produced in cortex and transported to basal ganglia.
brain derived neurotropic factor (BDNF)
Abnormal htt interferes with BDNF in 2 ways:
Inhibits the expression of the BDNF gene. Interferes with the transport of BDNF from the cerebral cortex to the BG
Neurons with inclusion bodies had _____ levels of abnormal htt elsewhere in the cell, cell lived longer than cells without inclusion bodies
Neurons with inclusion bodies had lower levels of abnormal htt elsewhere in the cell, cell lived longer than cells without inclusion bodies
Antibody that acts intracellularly (intrabody).
Targets a portion of the Htt protein.
Mouse models of HD, insertion of the ________ into brain suppressed production of mutant Htt and improved symptoms
Happ1
Degenerative brain disorder of unknown origin; causes progressive memory loss, motor deficits, and death. Severe degeneration of the hippocampus, entorhinal cortex and neocortex (prefrontal and temporal association areas), Locus coeruleus, Raphe nucleus .
Alzheimer’s Disease
Extracellular deposit containing a dense core of B-amyloid protein surrounded by degenerating axons and dendrites and activated microglia and reactive astrocytes.
Amyloid Plaque
a dying neuron containing intracellular accumulations of abnormally phosphorylated tau-protein filaments that formerly served as the cell’s internal skeleton.
Neurofibrillary Tangle
Alzheimer’s Disease
Amyloid plaques formed by defective β-amyloid protein (Aβ).
Gene encodes the production of the β-amyloid precursor protein (APP; ~700 a.a. long). APP is then cut in 2 places by secretases to produce β-amyloid protein. β-secretase γ-secretase Results in Aβ-40 or Aβ-42. Normal brain ~95% of Aβ is short. AD brain Aβ-42 is as high as 40%. Folds improperly and form aggregates. System cannot ubiquinate the high amounts of long Aβ proteins.
Gene for the amyloid beta precursor protein (APP) is located on chromosome 21, and people with trisomy 21 (Down Syndrome) who thus have an extra gene copy almost universally exhibit AD by 40 years of age.
APP gene – chromosome 21
glycoprotein that transports cholesterol in the blood and also plays a role in cellular repair
Apolipoprotein E (ApoE)
interfers with removal of long form of Aβ
ApoE4
Two presenilin genes found on chromosomes 1 and 14
Subunits of γ-secretase. Apolipoprotein E (ApoE) – glycoprotein that transports cholesterol in the blood and also plays a role in cellular repair. ApoE4 – interfers with removal of long form of Aβ.
______ is the cause of neural degeneration in Alzheimers
Aβ inside cell (not plaques) is the cause of neural degeneration.
Aggregated forms of amyloid (Aβ oligomers)
interact with microglia, causing an inflammatory response that triggers the release of toxic cytokines (chemicals produced by the immune system that destroy infected cells).
trigger XS release of glutamate by glial cells, causes excitotoxicity (increased inflow of Ca2+ through neural NMDA receptors.
Cause synaptic dysfunction and suppress the formation of LTP
Positive relationship b/w increased number of years of formal education and cognitive performance
The Religious Orders Study
Treatment for Alzheimer’s
Decline in Ach levels
Cholingeric agonists (acetylcholinesterase inhibitors).
NMDA receptor antagonist (memantine).
Immunotherapeutic approach.
Amyloid vaccine to reduce plaque deposits and improve performance on memory tasks in a transgenic mouse model.
Mixed results.
Dangerous side effects.
Attacks spinal cord and cranial nerve motor neurons.
10-20% caused by mutation in superoxide dismutase 1 (SOD1) – chromosome 21.
SOD1.
Toxic gain of function.
Protein misfolding and aggregation, impaired axonal transport, mitrochondrial dysfunction.
Impairs glutamate reuptake into glial cells – increased extracellular glutamate – excitotoxicity in motor neurons.
ALS
treatment for ALS
Riluzole.
Reduces glutamate-induced excitotoxicity.
Clinical trial – riluzole increased life-span ~2 months.
Autoimmune demyelinating disease.
Sclerotic plaques
Multiple Sclerosis
Treatment for MS
Interferon β.
Modulates the responsiveness of the immune system.
Treatment slows the progression and severity of the attacks.
Glaterimer acetate (copaxone).
Peptides composed of random sequences of glutamate, alanine and lysine.
May stimulate anti-inflammatory responses.
