Download doc Chapter 15 Notes

Chapter 15: Neurological Disorders
Notes taken by: Ashley Brown
Contact for mistakes: [email protected]
These notes probably suck (esp. near the end) and a lot of the time are essentially
copied straight from the book (10th edition btw) because I kind of just stare and take
notes at the same time, so they contain not the most brief of statements but yeah… I
still feel like I owe docuum a set of notes for saving my butt every exam. Enjoy,
happy studying, and hope these help!
Tumours
The major categories of neuropathological conditions that the brain can sustain are:
tumours, seizure disorders, cerebrovascular accidents, disorders of development,
degenerative disorders, and disorders caused by infectious diseases
Tumour: a mass of cells whose growth is uncontrolled and that serves no useful function
- malignant tumour: a cancerous tumour, it lacks a distinct border and may
metastasize
- benign tumour: a noncancerous tumour, it has a distinct border and cannot
metastasize
- the major difference between the two is whether the tumour is encapsulated or
has a distinct border between the mass of tumour cells and surrounding tissue
Metastasis: the processes by which cells break off tumours, travel through the vascular
system, and grow elsewhere in the body
Tumours damage brain tissue by two means: compression and infiltration
- both benign and malignant tumours can cause damage by compression
because they occupy space and push against the brain either destroying brain
tissue or indirectly blocking the flow of cerebrospinal fluid and causing
hydrocephalus
- malignant tumours also infiltrate by invading the surrounding region and
destroying cells in its path
- some are sensitive to radiation and can be destroyed by a beam of radiation
focussed on them
o in the brain they remove as much as possible and then target the
remaining cells with radiation
Tumours don’t arise from nerve cells (b/c they can’t divide) so they come other cells in
the brain or from metastasis. For types see TABLE 15.1 PAGE 522
- most serious types are metastases and the gliomas, which are usually very
malignant/fast growing
Glioma: a cancerous brain tumour composed of one of several types of glial cells
- glioblastoma multiformae: poorly differentiated glial cells
-
Astrocytoma: from astrocytes
ependymoma: from ependymal cells that line the ventricle
medulloblastoma: from cells in the roof of the fourth ventricle
oligodendrocytoma: from oligodendrocytes
Meningioma: a benign brain tumour composed of the cells that constitute the meninges
- tend originate in either the part of the dura mater b/t the two cerebral
hemispheres or along the tentorium (the sheet of dura mater b/t the occipital
lobe and cerebellum)
Seizure Disorders
Physicians use the term seizure disorder for epilepsy due to negative connotations
acquired in the past
- second most important category of neurological disorders (after strokes)
- see TABLE 15.2 PAGE 524 for categories
A seizure is a period of sudden, excessive activity of cerebral neurons
- if neurons that make up the motor system are involved it can cause a
convulsion
o a violent sequence of uncontrolled muscular movements caused by a
seizure
o most seizures do not cause these
Two important distinctions in seizure disorders: (1) partial vs. generalized seizures and
(2) simple vs. complex
- Partial seizures: a seizure that begins at a focus and remains localized, not
generalizing to the rest of the brain
o Definite focus or source of irritation (typically a scarred region from
an injury or a developmental abnormality such as a malformed blood
vessel)
o Neurons involved remained restricted to a small area
- Generalized seizures: a seizure that involves most of the brain, not just a
localized area
o Usually grow from a cous
Partial seizures can be simple or complex
- simple partial seizures: starts from a focus, remains localized, and doesn’t
lose consciousness
o involves changes in consciousness
- complex partial seizures start from a focus, remain localized but produce
loss of consciousness
Grand mal (or tonic-clonic seizures): a generalized seizure which is the most severe and
accompanied by convulsions
-
-
-
-
often before it starts they have warning symptoms like changes in moods or a
few sudden jerks upon awakening
a few seconds before it occurs the person can experience an aura which is a
sensation whose nature depends on the location of its focus
o effects having to do with what the area the focus does like if the
temporal lobe is where the focus is (which is in control of emotion)
they could suddenly feel angry or euphoric
tonic phase: the first phase of the grand mal seizure in which all of the
patient’s skeletal muscles contract
o sometimes there is an involuntary scream from muscles around the
lung contracting
o holds a rigid posture for about 15 seconds before entering the next
phase
clonic phase: the second phase in which the patient shows rhythmic jerking
movements
o literally means “agitated phase”
o muscles are trembling then jerking convulsively, quickly at first then
more and more slowly
o eyes roll, face is contorted with violent grimaces, tongue may be biten
o intense activity of ANS results in sweating and salivation
o after 30 seconds the patients muscles relax and then breathing begins
again
after clonic phase they fall into an unresponsive sleep for about 15 minutes
then may awake briefly only to fall back into an exhaustive sleep for a few
hours
Neural activity of a grand mal seizure:
- firing beigns in the focus at the time of the aura then spreads first to around
the focus then to the contralateral side through the corpus callosum
- then to the basal ganglia, the thalamus, and various nuclei of the brain stem
reticular formation
o the symptoms begin here
- the excited subcortical feed back more excitation to the cortex which
amplifies the activity there
- neurons in the motor cortex fire continuously  tonic phase
- diencephalic structures try to quench the seizure by sending inhibitory msg to
the cortex
o at first comes in brief burst  jerking of the clonic phase (as they
relax and contract again)
o burst of inhibition become more and more prolonged  jerking of
clonic phase occurs more slowly
o finally inhibition wins and they completely relax
Partial seizures involve smaller portions of the brain so their symptoms can include
sensory changes, motor activity, or both.
-
a seizure that begins in the occipital lobe may produce visual symptoms such
as spots of colors, flashes of lights or temporary blindness
in the parietal region it can evoke somatosensations such as feelings of pins
and needles or heat and cold
Absence (or petit mal seizures): a type of generalized seizure often seen in children;
characterized by periods of inattention, which are not subsequently remembered
- stop what they’re doing then stare off in the distance often blinking repeatedly
- unresponsive and normally don’t notice their attacks
- can occur up to several hundred times a day
- can go unnoticed
- can stop occurring when they reach adolescence
Seizures can cause brain damage, particularly the hippocampus. Damage is correlated
with the number and severity of seizures
- status epilepticus (a condition in which a patient undergoes a series of
seizures without regain consciousness) causes significant hippocampal
damage
o apparently damage caused by excessive release of glutamate during
the seizure (like an excitotoxic lesion)
Causes:
-
-
-
most common is scarring (from an injury, stroke, developmental abnormality,
or irritating effect of a growing tumour)
o most often seizures from injuries occur much after the injury itself(like
several months)
various drugs and infections that cause a high fever can also produce seizures
o high fevers in children particularly
o alcoholics or barbiturate addicts who suddenly stop using  sudden
lack of inhibition that they’re used to caused hyperactivity that can
cause the seizure
 NMDA receptor involved in seizures from alcohol withdrawal
 long-term suppression of NMDA (alcohol blocks the
receptor) causes supersensitivity (up-regulation) and without
alcohol the receptors suddenly rebound and are super active
and over fire
Genetic factors most involving ion channels
Most are caused by nongenetic factors or idiopathic (literally one’s own
suffering)
o Small brain abnormalities
Normally treated with anticonvulsant drugs, which work by increasing effectiveness of
inhibitory synapses. If the foci is super irritable, brain surgery is required.
Interesting because it is found sometimes after removing parts of the brain to eliminate
the seizure their neuropsychological functioning usually improves rather than exhibiting
behavioural deficits
- this can be explained because the regions surrounding the focus are constantly
trying to inhibit seizures a phenomenon referred to as interictal inhibition
(when the excitation wins over this inhibition is when a seizure occurs)
o this also suppresses normal functioning so when the foci is removed it
can stop inhibiting and therefore they function better
Many patients with seizures find relief in a ketogenic diet which is high in fats, moderate
in proteins, and low in carbs so the brain has less glucose but needs to rely on ketones
(compounds from broken down fats when blood glucose levels are low)
Cerebrovascular Accidents
Cerebrovascular accidents or strokes can produce impairments in perception, emotional
recognition and expression, memory, and language.
Likelihood of strokes is relative to age  probably doubles ever decade after 45 years.
Two major types: hemorrhagic and obstructive
- Hemorrhagic stroke: a cerebrovascular accident caused by the rupture of a
cerebral blood vessel
o Bleeding comes from a malformed blood vessel or one weakened
from high blood pressure)
o blood accumulates and puts pressure on surrounding brain tissue,
damaging it
- Obstructive stroke: a cerebrovascular accident caused by occlusion of a
blood vessel
o Ischemia: the interruption of the blood supply to a region of the body
o Caused by thrombi or emboli
 Thrombus: a blood clot that forms within a blood vessel,
which may occlude it
 Forms especially in blood vessels with previously
damaged walls
 If especially susceptible to formation people take
aspirin which helps prevent clot formation
 Embolus: a piece of matter (such as a blood clot, fat, or
bacterial debris) that dislodges from its site of origin and
occludes an artery
o Or caused by arteriosclerosis which is thickening of the arterial wall
Strokes cause permanent brain damage, depending on the size of the affected blood
vessel varying from negligible to massive.
Actions taken after strokes
-
hemorrhagic stroke from high blood pressure  medication to reduce it
hemorrhagic stroke from weak/malformed blood vessels  brain surgery that
seals off the faulty vessel to prevent further strokes
obstructive by thrombus  anticoagulant drugs that make blood less likely to
clot
obstructive by embolus from bacterial infection  antibiotics
We expect that the neurons die because they have been starved to death after being cut
off from oxygen and glucose but research shows that it is the presence of excessive
amounts of glutamate that kill the cells (as with excitotoxic lesions)
- sodium-potassium transporters that regulate the balance of ions in and out of
the cell stop functioning from lack of fuel
- the membrane depolarises and causes excessive release of glutamate
- this excessive glutamate triggers excessive influx of Na+ and Ca2+ ions into by
way of NMDA receptors which is toxic to the cell
o intracellular sodium causes the cell to absorb water and swell
o inflammation attracts white blood cells which obstruct capillary walls
- damaged mitochondria produce free radicals (molecules with unpaired
electrons that act as powerful oxidizing agents) which are extremely toxic to
cells, destroying nucleic acids, proteins, and fatty acids
Ways to minimize the amount of brain damage caused by strokes:
- administer drugs that dissolve blood clots in attempt to re-establish circulation
to an ischemic brain region
o some success  tPA (tissue plasminogen activator – a clot-dissolving
drug) administration after the onset of a stroke has clear benefits if
given within 3 hours of stroke
 this enzyme works by converting plasminogen (a protein in
blood) to plasmin which dissolves fibrin (a protein involved in
clot formation)
 research shows it has toxi effects in the CNS
o with Desmodus rotundus plasminogen activator (DPSA) or
desmoteplase is an anticoagulant that appears to have no excitotoxic
injuries and can restore blood flow and reduce clinical symptoms if
given up to nine hours after onset of stroke
Prevention  reducing risk factors by taking medication or changing lifestyle to reduce
risk from high blood pressure, cigarette smoking, diabetes, and high blood levels of
cholesterol
Atherosclerosis is a precursor to stokes and heart attacks
- linings of arteries develop a layer of plaque which consist of deposits of
cholesterol, fats, calcium, and cellular waste
- makes arteries more vulnerable to being blocked, and greatly increase the risk
of massive strokes
- the internal carotid artery is sensitive to this
o may need carotid endarterectomy which removes the plaque by
cutting a hole in the neck and such
o or placing a stent in the artery which doesn’t involve cutting open the
neck they insert it using a catheter (a flexible plastic tube) and string
its way from an artery in the groin then expand the stent when its in
place, opening the narrowed artery
Depending on the location of brain damage, people with strokes receive physical therapy
and sometimes speech therapy to help recover
- forcing patients to use impaired arm by putting other in a sling, which is a
procedure called constraint-induced movement therapy, causes long term
improvement in using the affected arm
o causes changes in the connections of the primary motor cortex
Disorders of Development
Brain development can be aversely affected by presence of toxic chemicals during
pregnancy and by genetic abnormalities (both hereditary and nonhereditary) which can
result in mental retardation
Toxic Chemicals
A common cause of mental retardation is the presence of toxins that impair fetal
development during pregnancy.
- ex: if during pregnancy the mother contracts rubella or German measles, toxic
chemicals released from the virus interfere with the chemical signals that
control normal development of the brain
- various drugs adversely affect fetal development
Fetal alcohol syndrome: a birth defect caused by ingestion of alcohol by a pregnant
woman; includes characteristic facial anomalies and faulty brain development
- women don’t need to be alcoholics to cause this, a single alcoholic beverage
during a critical period can cause it
Alcohol disrupts normal brain development by interfering with a neural adhesion
protein which plays a role in brain development by helping to guide the growth of
neurons
Prenatal exposure to alcohol also appears to have direct effects on neural plasticity
Inherited Metabolic Disorders
Errors of metabolism refer to genetic abnormalities in which an enzymes instructions are
messed up so it can’t be synthesized
Phenylketonuria (PKU): a hereditary disorder caused by the absence of an enzyme that
converts the amino acid phenylalanine into tyrosine. The accumulation of phenylalanine
causes brain damage unless a special diet is implemented soon after birth
- most common and best know of the metabolism disorders
- a lot of phenylalanine in the blood interferes with the myelinisation of neurons
in the CNS and because this myelination take place after birth and so if infants
with PKU consume food containing phenylalanine they’ll develop severe
mental retardation (an average IQ of 20 at age 6)
- if a mother has PKU she must follow a strict diet or her baby will have severe
brain damage (because her brain is fine now but it’ll hurt her baby)
- new bourns are tested for this immediately
Pyridoxine dependency: a metabolic disorder in which an infant requires larger-thannormal amounts of pyridoxine (vitamin B6) to avoid neurological symptoms
- untreated results in damage to cerebral white matter, to the thalamus, and to
the cerebellum
Galactosemia: an inherited metabolic disorder in which galactose (milk sugar) cannot
easily be metabolized
- untreated causes damage to the cerebral white matter and to the cerebellum
- treatment involves use of a milk substitute that does not contain galactose
- don’t confuse with lactose intolerance which is caused by insufficient
production of lactase so they can’t break down lactose, causing digestive
problems not brain damage
Tay-Sachs disease: a heritable, fatal, metabolic storage disorder; lack of enzymes in
lysosomes causes accumulation of waste products and swelling of cells of the brain
- lysosomes gets larger as they accumulate waste causing eventual swelling of
the brain
Down Syndrome
Down syndrome is a congenital disorder (present at birth) caused by the presence of an
extra twenty-first chromosome, characterized by moderate-to-severe mental retardation
and often by physical abnormalities
- closely associated with the mother’s age  something goes wrong with ova
resulting in presence of 2 rather than one 21st chromosome (with dad’s there is
now 3)
- extra chromosome causes biochemical changes that impair normal brain
development
o can be detected by amniocentesis
Distinguishing features:
- round heads, thick protruding tongues that tend to keep mouth open much of
the time, stubby hands, short statue, low-set ears, somewhat slanting eyelids
- slow to learn to talk but most do by 5 years old
-
brains are approx. 10 percent lighter, convolutions are simpler and smaller
frontal lobes are small and superior temporal gyrus (Wernicke’s area) is
thinner
After age 30 brain begins degenerating similar to Alzheimer’s disease
Some study found that injects of drugs that serve as GABA antagonists it increased both
LTP and performance on declarative learning task on some mice with downs.
Degenerative Disorders
Many disease processes cause degeneration of the cells of the brain
Transmissible Spongiform Encephalopathies
Transmissible spongiform encephalopathy (TSE): a contagious brain disease who
degenerative process gives the brain a spongelike appearance; caused by the
accumulation of misfolded prion protein
- Different forms:
o Bovine Spongiform encephalopathy (BSE) or mad cow disease
o Creutzfeldt-Jakob disease – which is transmitted to humans from cows
o Fatal familial insomnia
o Kuru – affects humans only
 Transmitted through cannibalism
o Scrapie – affects mainly sheep (no humans)
- Transferred by prions rather than microorganisms like other transmissible
diseases
o Prions: a protein that can exist in two forms that differ only in their
three-dimensional shape; “protein infectious agents” (sequence of
infectious and non-infectious prions are identical)
o They are found primarily in the membrane of neurons, where they play
a role in synaptic function
o Resistant to proteolytic enzymes, which destroy proteins by breaking
the peptide bonds
o Also resistant to levels of heat that denature normal proteins (why
cooking meat doesn’t destroy BSE)
o Once a misfolded prion is introduced into a cell it causes the normal
prion to become misfolded as well
- Symptoms include dementia (loss of memory and personality; hallucinations),
speech impairment, ataxia (changes in gait, rigid posture), and seizures
A familial form of Creutzfeldt-Jakob disease is transmitted as a dominant trait but most
cases it is a sporadic disease, or a disease that occurs rarely and is not obviously caused
by heredity or an infectious agent.
- prion protein diseases are special because they can be genetic or sporadic and
that either of these forms can be transmitted to other
Prions don’t seem to be essential for the life of a cell
- normal prion protein plays a role in neural development and differentiation in
fetuses and neurogenesis in adults
- suggested prionlike mechanism could play a role in the establishment and
maintenance of long-term memories
The conversion of normal prions to infectious prions is what kills the cells. The mere
presence of PrPSc (the bad one) in the cell doesn’t cause the disease.
The accumulation of misfolded proteins could be a signal for apoptosis
- caspase: a “killer enzyme” that plays a role in apoptosis or programmed cell
death
Parkinson’s Disease
Parkinson’s disease (PD) is caused by degeneration of the nigrostriatal system.
Primary symptoms: muscular rigidity, slowness of movement, a resting tremor, and
postural instability.
- resting tremor: vibratory movements of the arms and hands, accompanied by
rigidity
Lewy body: abnormal circular structures with a dense core consisting of α-synuclein
protein surrounded by a halo of radiating fibers
- found in the cytoplasm of nigrostriatal neurons in people with Parkinson’s
disease
- α-synuclein: a protein normally found in the presynaptic membrane, where it
is apparently involved in synaptic plasticity. It’s their abnormal accumulation
that is the cause of neural degeneration seen in PD
o produced by a mutation of a gene on chromosome 4
o toxic gain of function: something that is said of a dominant mutation
that involves a faulty gene that produces a protein with toxic effects
o the protein becomes misfolded and causes aggregations in dominergic
neurons
Another hereditary form of PD is caused by a mutation of a gene on chromosome 6 that
produces a gene that has been named parkin
- parkin: a protein that plays a role in ferrying defective or misfolded proteins
to the proteasomes
o proteasomes: an organelle responsible for destroying defective or
degraded proteins within the cell
- parkin assist in tagging of abnormal/misfolded proteins with numerous
molecules of ubiquitin (in a process called ubiquitination)
o ubiquitin: a protein that attaches itself to faulty or misfolded proteins
and thus targets them for destruction by proteasomes
-
causes loss of function: said of a genetic disorder caused by a recessive gene
that fails to produce a protein that is necessary for good health
dopaminergic neurons are particularly sensitive to the accumulation of
abnormal proteins
The major majority of PD are sporadic or they occur in people without a history of PD.
- suggested its caused by toxins present in the environment, by faulty
metabolism, or by unrecognized infectious disorders
Treatments:
- standard treatment is L-DOPA which is the precursor of dopamine
o an increased level of L-DOPA in the brain causes the remaining
dopaminergic neurons to produce and secrete more dopamine which
alleviates the symptoms of PD for a time
o does not work indefinitely
 eventually the number of nigrostriatal dopaminergic neurons
declines to a really low level and the symptoms get much
worse
 high levels of L-DOPA produces side effects because it works
on dopaminergic neurons not in the nigrostriatal region
- deprenyl is often given in conjunction with L-DOPA
o inhibits the activity of the enzyme MAO-B
o There was that case that people who took an illicit drug contaminated
with MPTP acquired the symptoms of PD and these symptoms were
alleviated by deprenyl
o There is an age-related increase in MAO-B activity that might increase
levels of oxidative stress in dopaminergic neurons
- Transplantation of fetal tissue
o Attempts to re-establish the secretion of dopamine in the neostriatum
o Takes tissue obtained from the substantia nigra of aborted fetuses and
implants into the caudate nucleus and putamen by stereotaxically
guided needles
o Not used much because many patients have shown persistent
dyskinesias or troublesome and often painful involuntary movements
- A potential source of dopamine cells could come from cultures of stem cells
o Stem cells are undifferentiated cells and therefore can develop into a
lot of different cell types
o With monkey studies they not only became dopaminergic neurons but
astrocytes and other cells that protect and repair cells  they showed
improved motor behaviour
- Pallidotomy (destruction of the internal division of the globus pallidus) or
destruction of the subthalamic nuclei
o internal division of the globus pallidus (GPi): a division of the
globus pallidus that provides inhibitory input to the motor cortex via
the thalamus
-
o this surgery often reduces the rigidity and enhances the patients ability
to move but sometimes makes the symptoms worse and causes partial
blindness
o get better at the surgery and it is now used to treat younger patients
with PD who no longer respond to L-DOPA
o the subthalamic nucleus has an excitatory effect on the GPi
implanting electrodes in the subthalamic nucleus and attaching a device that
permits the patient to electrically stimulate the brain through electrodes
o no evidence of cognitive deterioration from deep brain stimulation
Akinesisa, or difficulty in initiating movements, is associated with decreased activation of
the supplementary motor area
Tremors are associated with abnormalities of a neural system involving the pons,
midbrain, cerebellum and thalamus
Huntington’s Disease
Huntington’s disease: an inherited disorder that causes degeneration of the basal
ganglia; characterized by progressively more severe uncontrollable jerking movements,
writhing movements, dementia, and finally death
- symptoms normally begin the person’s 30s or 40s
- first signs of neural degeneration occur in a specific group of inhibitory
neurons in the putamen  GABAergic medium spiny neurons
o damage to these neurons removes some inhibitory control exerted on
the premotor and supplementary motor areas of the frontal cortex 
leads to involuntary movements
- as the disease progresses other regions of the brain incl. the cerebral cortex
show neural degeneration
Hereditary disorder caused by a dominant gene on chromosome 4
- defect is a repeated sequence of bases that code for the amino acid glutamine
- repeated sequence causes the gene product (which is a protein called
huntingtin) to contain an elongated stretch of glutamine
o huntingtin (htt): a protein that may serve to facilitate the production
and transport of brain-derived neurotrophic factor
o longer stretches of glutamine are associated with patients who’s
symptoms begin at an early age
o toxic gain of function  the abnormal htt causes the harm
- the cause of death in the cells is apoptosis
o abnormal htt may trigger this by impairing the function of the
ubiquitin-protease system (which activates caspase, one of the
enzymes involved in apoptosis)
Normal htt is found all over the body especially in neurons and cells of the testes
- protein plays a critical role in development
-
most important function of htt in adulthood appears to be the facilitation of the
production and transport of brain-derived neurotrophic factor (BDNF)
o BDNF is a chemical that is necessary for survival of neurons in the
caudate nucleus and putamen
o BDNF is produced in the cerebral cortex and transported to the basal
ganglia
o The presence of abnormal htt inhibits the expression of BDNF
o Abnormal htt also interferes with the transport of BDNF from the
cerebral cortex to the basal ganglia
Inclusion bodies: misfolded htt in the nucleus
-
accumulate during the development of the disease
a study suggest these actually protect neurons
At present there is no treatment for Huntington’s disease.
Alzheimer’s Disease
Dementia: a loss of cognitive abilities such as memory, perception, verbal ability, and
judgement commonly caused by strokes or Alzheimer’s disease
Alzheimer’s disease: a degenerative brain disorder of unknown origin; causes
progressive memory loss, motor deficits, and eventual death
- memory deficit most critically involves recent events, resembling the
anterograde amnesia of Korsakoff’s syndrome
- produces severe degeneration of the hippocampus, entorhinal cortex,
neocortex (esp. the association cortex of the frontal and temporal lobes),
nucleus basalis, locus coeruleus, and raphe nuclei
- the sulci in their brains are much wider  substantial loss of cortical tissue
The brains of patients with both down syndrome and Alzheimer’s disease develop similar
abnormal structures: amyloid plaques and neurofibrillary tangles
- amyloid plaque: an extracellular deposit containing a dense core of βamyloid protein surrounded by degenerating axons and dendrites and
activated microglia and reactive astrocytes
o β-amyloid (Aβ): a protein found in excessive amounts in the brains of
patients with Alzheimer’s disease
o eventually the phagocytic glial cells destroy the degenerating axons
and dendrites just leaving the core of Aβ protein
- Neurofibrillary tangle: a dying neuron containing intracellular
accumulations of hyperphosphorylated tau-protein filaments that formerly
served as the cell’s internal skeleton
o Tau protein: a protein that normally serves as a component of
microtubules, which provide the cell’s transport mechanism and
cytoskeleton
o During the progression of Alzheimer’s disease, excessive amounts of
phosphate ions attach to stands of tau protein, changing it’s molecular
structure
o These abnormal filaments are seen in the soma and proximal dendrites
of pyramidal cells in the cerebral cortex, disrupting the transport of
substances within the cell, the cell then dies, leaving a tangle of protein
filaments
Formation of amyloid plaques is caused by production of a defective form of Aβ
- first a gene encodes the production of β-amyloid precursor protein (APP)
- then APP is cut apart in two places by secretases (a class of enzymes that cut
the APP into smaller fragments, including Aβ
o first the β-secretase cuts the “tail” off an APP molecule
o second the γ-secretase cuts the “head” off
 location of this cut determines which form is produced
 result is a molecule of Aβ that contains 40 or 42 amino acids
 normal brain has 90-95% short form and remaining are
long, in patients with Alzheimer’s disease the proportion of
long Aβ rises to as much as 40%
 high concentration of long from Aβ have a tendency to fold
themselves improperly and form aggregations which have a
toxic effect on cells
Acetylcholinergic neurons in the basal forebrain are among the first cells to be affected in
AD
- Aβ serves as a ligand for the p75 neurotrophin receptor which normally
responds to stress signals and stimulates apoptosis
o Levels of this receptor are high in basal forebrain ACh neurons
Because at least some forms of AD runs in families and it shares similarities with down
syndrome it has been hypothesized that the 21st chromosome might be involved
Presenilin: a protein produced by a faulty gene that causes APP to be converted to the
abnormal short from
- may be the cause of Alzheimer’s disease
Apolipoprotein E (ApoE): a glycoprotein that transports cholesterol in the blood and
plays a role in cellular repair; presence of the E4 allele of the ApoE gene increases the
risk of late-onset Alzheimer’s disease
- interferes with the removal of the long form of Aβ
- presence of a mutated gene exacerbate the risk factors of traumatic brain
injury, obesity, hypertension, high cholesterol levels, and diabetes
Appears that excessive amounts of Aβ but not tau protein are responsible for the disease
even though they excesses of both.
-
specifically the presence of excessive amounts of Aβ in the cytoplasm of cells,
not in the formation of amyloid plaques themselves, is the cause of neural
degeneration
Increase in Aβ and the subsequent degeneration are first seen in regions with the highest
default activity (activity that occurs when a person is resting and not working on a task or
solving a problem)
Most forms of AD are sporadic not hereditary.
- most prevalent non-genetic risk factor is traumatic brain injury
- education level has been shown to play an important role  formal education
appears to enable a person to maintain a higher level of cognitive performance
even in the face of brain degeneration
Only approved pharmacological treatments for AD are acetylcholinesterase inhibitors and
an NMDA receptor antagonist
Some stuff about immune system that went over my head, read it yourself if you’re too
concerned (I’m not) – page 547 – 548
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS): a degenerative disorder that attacks the spinal
cord and cranial nerve motor neurons
- symptoms: spasticity (increased tension of muscles, causing stiff and awkward
movements), exaggerated stretch reflexes, progressive weakness, and
muscular atrophy, and, finally, paralysis
o death normally occurs 5 to 10 years after onset of the disease as a
result of failure of respiratory muscles
o muscles that control eye movement are spared
o cognitive abilities are rarely affected
10% cases of ALS are hereditary, the other 90% are sporadic
A mutation on chromosome 21 in the gene that produces superoxide dismutase 1 (SOD1)
causes some cases of the hereditary ALS
- causes a toxic gain of function that leads to protein misfolding and
aggregation, impaired axonal transport, and mitochondrial dysfunction
- also impairs glutamate reuptake into glial cells, so more extracellular levels of
glutamate cause excitotoxicity in motor neurons
Primary cause of sporadic ALS appears to be an abnormality in RNA editing that messes
with a particular glutamate receptor subunit (GluR2) that results in an overall motor
neuron from excitotoxicity
Treated by riluzole which reduces glutamate induced excitotoxicity
Insulin-like growth factor-1 might also work
Multiple Sclerosis
Multiple sclerosis (MS) is an autoimmune demyelinating disease
- the immune system attacks the myelin sheaths and leaves behind hard patches
of debris called sclerotic plaques
- normal transmission of neural messages is interrupted
Affects women more frequently than men, occurring in the late 20s or 30s
Only two treatments show promise (neither halts the progression of MS though)
- interferon β  a protein that modulates the responsiveness of the immune
system
o when administered it reduces the frequency and severity of attacks and
slows the progression of neurological disabilities
o only partially effective
- glatiramer acetate  a mixture of synthetic peptides
o causes immune system to secrete anti-inflammatory chemicals such as
interleukin 4 which suppresses the activity of cells that would destroy
the myelin sheaths
Korsakoff’s Syndrome
Neither hereditary or contagious, it is caused by environmental factors, usually chronic
alcoholism
Results from a thiamine (vitamin B1) deficiency caused by alcoholism
- both from poor diet and the fact that alcohol interferes with intestinal
absorption of thiamine
- essential for a step in metabolism  the carboxylation of pyruvate, an
intermediate product in the breakdown of carbohydrates, fats and amino acids
Brain damage causes anterograde amnesia
- disease is characterized by degenerated mammillary bodies which are located
at the base of the brain, in the posterior hypothalamus
Disorders Caused by Infectious Diseases
Encephalitis: an inflammation of the brain; caused by bacteria, viruses, or toxic
chemicals
- most commonly from a virus transmitted by mosquitos
- symptoms: fever, irritability and nauseam followed by convulsions, delirium,
and signs of brain damage such as aphasia or paralysis
- can also be caused by herpes simplex virus (the cause of cold sores)
-
two forms of viral encephalitis: polio and rabies
o Acute anterior poliomyelitis (polio): a viral disease that destroys
motor neurons of the brain and spinal cord
o Rabies: a fatal viral disease that causes brain damage; usually
transmitted through the bite of an infected animal
 Symptoms: a short period of fever and headache, followed by
anxiety excessive movement and talking, difficulty in
swallowing, movement disorders, difficulty in speaking,
seizures, confusion, and finally death (within 2 to 7 days after
onset of symptoms)
 Virus particularly attracted to cells in the cerebellum and
hippocampus
 Incubation period for rabies last for several months as the virus
climbs through the peripheral nerves and a vaccine can be
given during this time
Acquired immune deficiency syndrome (AIDS) is not a CNS disease but it is an
infectious disease that causes brain damage which results in a syndrome called AIDS
dementia complex (ADC) which is characterized by damage to synapses and death of
neurons in the hippocampus, cerebral cortex, and basal ganglia
- loss of cognitive and motor functions
- not HIV that infects the neurons but the glycoprotein gp120 envelope that
coats the RNA is responsible
Meningitis: an inflammation of the meninges; can be caused by viruses or bacteria
- symptoms: headache, stiff neck, convulsions, confusion or loss of
consciousness, and sometimes death
- usual cause is the spread of a middle-ear infection into the brain, introduction
of an infection into the brain from a head injury, or the presence of emboli that
have dislodged from a bacterial infection present in the chambers of the heart
(from unclean hypodermic needles)
- inflammation can damage brain by interfering with circulation of blood or
blocking the flow of CSF through the subarachnoid space causing
hydrocephalus
- antibiotics can successfully treat bacterial meningitis