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Important Points!
Website: http://play.psych.mun.ca Course outline Course lectures Study questions Course info (i.e. change of exam date, class cancelled,
assignment info, etc)
Not time in class to cover all material in text, but students are responsible for text and class material for midterms and exams.
Students are responsible for all material covered in class (but not in text).
Chapter 15: Neurological Disorders
Preview
Tumors
Seizure Disorders
Cerebrovascular Accidents
Disorders of Development
Degenerative Disorders
Disorders Caused by Infectious Diseases
Tumors Introduction
Tumor – a mass of cells whose growth is uncontrolled and that serves no useful function.
Malignant Tumor – a cancerous tumor; lacks distinct border and may metastasize.
Benign Tumor – a noncancerous tumor; has a distinct border and cannot metastasize.
Metastasis – process by which cells break off of a tumor, travel through the vascular system, and grow elsewhere in the body.
Metastatic Tumor
Tumors (Continued)
Glioma – a cancerous brain tumor composed of one of several types of glial cells. Malignant gliomas contain tumor initiating cells
which originate from transformations of neural stem cells
Rapidly proliferate and give rise to a glioma Meningioma – a benign brain tumor composed of
the cells that constitute the meninges.
Malignant Glioma
Malignant Meningioma
Tumors
Tumors can damage brain tissue by 2 means:
Compression Directly Indirectly - blocking flow of CSF, hydrocephalus
Infiltration
Preview
Tumors
Seizure Disorders
Cerebrovascular Accidents
Disorders of Development
Degenerative Disorders
Disorders Caused by Infectious Diseases
Seizure Disorders
Epilepsy - Primary symptom is seizures, but not all who have seizures have epilepsy
Affects about 1% of the population
Difficult to diagnose due to the diversity and complexity of epileptic seizures
Seizures
Seizures often preceded by an aura, such as a smell, hallucination, or feeling Aura’s nature suggests the epileptic focus Warns epileptic of an impending seizure
Seizures
Partial seizures– does not involve the whole brain, has a definite focus, or source of irritation Scarred region caused by old injury or
developmental abnormality (malformed blood vessel)
Generalized epilepsy – involves the entire brain, widespread. Often grow from a focus (may be unknown)
Partial Seizures
SimpleSimple Symptoms are primarily sensory or motor or both Symptoms spread as epileptic discharge spreads Not associated with a loss of consciousness
Complex Complex Often restricted to the temporal lobes
(temporal lobe epilepsy) Patient engages in compulsive and repetitive
simple behaviors (automatisms) Lead to loss of consciousness
Figure 15.6 Primary Motor Cortex and Seizures
Generalized Seizures Grand malGrand mal
Loss of consciousness
Tonic-clonic convulsions Rigidity (tonus)
~15 s All muscles contract, arms are
rigidly outstretched Tremors (clonus) ~ 30 s
Muscles begin trembling, jerking – quick at first, then slower, eyes roll, face is contorted, tongue may be bitten, sweating, salivation.
Firing begins at focus spreads to other regions Corpus callosum
Resulting hypoxia may cause brain damage
Generalized Seizures
Absence (Petit mal) Absence (Petit mal) Common in children Not associated with convulsions A disruption of consciousness associated with a cessation
of ongoing behavior Unresponsive, usually do not notice their attacks Can occur several hundred times/day
Seizures Can cause brain damage
~ 50% of patients with seizure disorders show damage to the hippocampus Amount of damage – correlated with the number and severity
of seizures
Status Epilepticus – a condition in which a patient undergoes a series of seizures without regaining consciousness
May cause significant hippocampal damage
Caused by excessive release of glutamate during seizure
Causes of seizures
Injury, stroke, developmental abnormality, effect of a growing tumor
Febrile seizures Infantile fever
~3% of children under 5
Alcohol or barbiturate withdrawal Sudden release of the inhibiting effects of
alcohol or barbiturate leaves the brain in a hyper-excitable condition (can be fatal)
Causes of seizures Alcohol effects (during
intoxication) GABA activation NMDA blocked
Alcohol Withdrawal Glutamate rebound NMDA receptors
Causes of Seizures
Genetic factors (not common cause)
70 genes (as of now) associated with seizure disorders
Nearly all genes identified control the production of ion channels
Treatments
Anticonvulsant drugs (increasing effectiveness of inhibitory synapses)
Brain surgery – remove region of the brain surrounding the focus (usually located in MTL)
Kindling Model of Epilepsy
A series of alternating bilateral brain stimulations eventually elicits convulsions – the kindling phenomenon Typically amygdala or hippocampus Neural changes are permanent Produced by stimulation distributed over time
Convulsions are similar to those seen in some forms of human epilepsy – but they only occur spontaneously if kindled for a very long time
Kindling phenomenon is comparable to the development of epilepsy (epileptogenesis) seen following a head injury
Ronald J RacineMcMaster University
Preview
Tumors
Seizure Disorders
Cerebrovascular Accidents
Disorders of Development
Degenerative Disorders
Disorders Caused by Infectious Diseases
3rd leading cause of death
Most common cause of adult disability
Common consequences of stroke◦ Amnesia, aphasia, paralysis, coma
Infarct – area of dead or dying tissue produced by the stroke
Penumbra – dysfunctional area surrounding the infarct ◦ Goal of treatment following stroke is to save the penumbra
Stoke
Cerebrovascular Accidents
Incidence in US – 750,000/year
1-2% by 75
2 major causes: Hemorrhagic ischemic
Cerebrovascular Accidents
Hemorrhagic Hemorrhagic StrokesStrokes Cerebrovascular 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
Fig. 15.7
Bleeding in the brain
Cerebral blood vessel ruptures and blood seeps into the surrounding neural tissue
Cause bursting aneurysm
Aneurysm 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 poisons or infection Weakened blood vessel from high blood pressure
Cerebral Hemorrhage
Cerebrovascular Accidents
Ischemic StrokeIschemic Stroke – cerebrovascular accident caused by occlusion of a blood vessel
Thrombus Thrombus – blood clot that forms within a blood vessel, which may occlude it.
EmbolusEmbolus – piece of material that forms in one part of the vascular system, breaks off, carried by blood stream until it reaches a smaller artery
Ischemia Ischemia – interruption of the blood supply to a region of the body.
Fig. 15.7
“Cerebral Penumbra”Nature Medicine (2008) 14:497-500
Does not develop immediately
Most damage is a consequence of excess neurotransmitter release – especially glutamate
Blood-deprived neurons become overactive and release glutamate
Ischemia-induced brain damage takes time does not occur equally in all parts of
the brain mechanisms of damage vary with the
brain structure affected
Damage Due to Cerebral Ischemia
Blood supply interrupted Oxygen, glucose and
glycogen depleted Na+/K+ transporters stop
working Depolarizes the cell
lnflux of Na+ and Ca2+ triggers the release of still more
glutamate a sequence of internal
reactions that ultimately kill the neuron
Causes cell to swell
Inflammatory responses Microglia- phagocytosis Astrocytes- scarring
Generation of free radicals Toxic substances Destroy nucleic acids,
proteins and fatty acids
Treatment for Ischemic injury
Clot dissolving drugs Tissue plasminogen activator (tPA) – within 3
hrs Can have neurotoxic effects Desmoteplase (anticoagulant; vampire bats)
Not toxic, up to 9 hrs
Hypothermia Animal models show that hypothermia has
neuroprotective effects Corbett (MUN) Slow to catch on in
human treatment
Treatment for Ischemic injury
Animal models of stroke and ischemic injury Gerbil, rat
Biernaskie and Corbett (2001) Enriched environment and post-ischemic training Animals housed in
enriched environments and subjected to training with affected limb showed enhanced dendritic complexity and length
Motor assessment: EE plus training rats were indistinguishable from control 4 and 9 weeks after ischemia
Enriched environment : Corbett (MUN)
Treatment for Ischemic injury
Physical therapy Human studies
Taub et al (2006) Constraint-induced
movement therapy Researchers put the good
arm into a sling for 2 weeks after ischemic injury
Forced patients use the affected arm
Controls: relaxation and fitness exercise
CI therapy – changes in connections of primary motor cortex
See Fig. 15.11
Preview Tumors
Seizure Disorders
Cerebrovascular Accidents
Disorders of Development Toxic chemicals Inherited metabolic disorders Down Syndrome
Degenerative Disorders
Disorders Caused by Infectious Diseases
Toxic Chemicals
During pregnancy, impairs fetal development Mother contracts rubella (German measles)
Toxin produced by virus Mental retardation
Mother ingests alcohol during pregnancy Mental retardation Babies are smaller, and develop more slowly Fetal alcohol syndrome – abnormal facial development,
deficient brain development Neural adhesion protein – protein that helps guide the
growth of neurons in developing brain Decreased plasticity in rats (decreased LTP) Alters development of neuronal stem cells
Inherited Metabolic Disorders
At least 100 Phenylketonuria (PKU)
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 Treatment
Low-phenylalanine diet
Inherited Metabolic Disorders
Tay-Sachs disease 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
Genetic accident
~0.15% of births
Usually occurs during ovulation Extra chromosome 21 is created in the egg
3 chromosome 21s in the zygote
Down Syndrome
Probability increases with advancing maternal age
Down Syndrome
Trisomy 21 Caused by a nondisjunction event. a gamete (a sperm or egg cell) is produced with an extra copy of
chromosome 21 Cause of approximately 95%
88% from nondisjunction in the maternal gamete 8% from nondisjunction in the paternal gamete.
Nondisjunction is the failure of chromosome pairs to separate properly during cell division
The result of this error is a cell with an imbalance of chromosomes
Genetics of DS
Mosaicism
When some of the cells in the body are normal and other cells have trisomy 21
This can occur in one of two ways:1. Nondisjunction event during early cell division in a normal embryo leads
to a fraction of the cells with trisomy 21
2. Down syndrome embryo undergoes nondisjunction and some of the cells in the embryo revert to the normal chromosomal arrangement.
Variability in the fraction of trisomy 21, both as a whole and among tissues.
Cause of 1–2%
Down Syndrome
Robertsonian translocation
The long arm of chromosome 21 is attached to another chromosome, often chromosome 14 or itself (called an isochromosome) A person with such a translocation is phenotypically normal.
During reproduction, there is a significant chance of creating a gamete with an extra chromosome 21
Cause of 2–3% of observed cases of Down syndrome.
No maternal age effect, and is just as likely to have come from fathers as mothers.
Down Syndrome
Duplication of a portion of chromosome 21
Region of chromosome 21 will undergo a duplication (rare)
Leads to extra copies of some, but not all, of the genes on chromosome 21
If the duplicated region has genes that are responsible for Down syndrome physical and mental characteristics, such individuals will show those characteristics
Very rare
Down Syndrome
Consequences Disfigurement
Flattened skull and nose Folds of skin over the inner corners
of the eyes Short fingers
Retarded intellectual development Often serious medical complications
Down Syndrome
Preview
Seizure Disorders
Cerebrovascular Accidents
Disorders of Development
Degenerative Disorders variant Creutzfeldt-Jackob (BSE) Parkinson’s Disease Huntington’s Disease Alzheimer’s Disease Multiple Sclerosis
Disorders Caused by Infectious Diseases
Degenerative Disorders: vCJD
Transmissible Spongiform Encephalopathies Contagious brain disease whose degenerative
process gives the brain a sponge-like appearance. Bovine Spongiform Encephalopathy (BSE) Creutzfeldt-Jakob Disease (CJD) Fatal familial insomnia Kuru (humans) Scrapie (sheep)
Prions – protein that can exist in two forms that differ only in their 3-D shape. Stanley Prusiner (discovered 1986) Nobel Prize (1997)
Normal prion protein (synaptic protein) Development and learning and memory Accumulation of misfolded prion protein is
responsible for TSE.
PRION DISEASESPRION DISEASES
PrPc (normal) and PrPsc (prion infected)
PrPSC -protease-resistant (prion protein also heat resistant)
Abnormal protein taken up into neuron by retrograde transport
PrPC PrPSC
Transmissible Spongiform Transmissible Spongiform EncephalopathiesEncephalopathies Encephalopathies
Encephalopathy gives the brain a ‘swiss cheese’-like appearance
Once introduced into the cell the PrPsc can cause the PrPc (normal) to become misfolded
APOPTOSISAPOPTOSIS: programmed cell death Caspases: enzymes generated
by the cell initiating cell death BSE: caspase 12
Transmissable Spongiform Encephalopathy
HUMAN PRION HUMAN PRION DISEASESDISEASES
Creutzfeldt-Jakob (and vCJD)
Fatal familial insomnia Autosomal dominant
40 families; affecting ~100 people
Kuru Fore people of Papa New Guinea; cannabalism
Creutzfeldt-Jakob Disease (CJD)
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)
Three recognized methods of affliction Familial Sporadic Acquired
Iatrogenic Variant (a.k.a. New Variant)
Long incubation periods (4-40 years) Species Barrier and multiple exposures
FOOD FOR THOUGHT
50,000 BSE-infected cattle are estimated to have entered the human food chain before its recognition in 1986
“You’re sick, Jessy!…Sick, sick, sick!”
vCJD: Age of Onset
British Medical Journal 2001; 322 : 841
vCJD: EpidemiologyvCJD: Epidemiology
BMJ 2001; 323 : 858