Important Points!
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Chapter 15: Neurological Disorders
Preview
 Tumors
 Seizure Disorders
 Cerebrovascular Accidents
 Disorders of Development
 Degenerative Disorders
Tumors
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.
 Glioma – a cancerous brain tumor composed of one of
several types of glial cells.
 Meningioma – a benign brain tumor composed of the
cells that constitute the meninges.
Seizures
 Partial seizures– does not involve the whole brain
 Generalized seizures – involves the entire brain, widespread.
 Simple
 Complex
 Grand mal – generalized, tonic/clonic
 Absence (Petit mal) – generalized, absence of behavior
 Causes:
 Injury, stroke, developmental abnormality, effect of a growing tumor
 Febrile seizures
 Infantile fever
 Alcohol or barbiturate withdrawal
 Genetic factors
 Treatment - Anticonvulsant drugs, surgery, diet
Cerebrovascular
Accidents
 Hemorrhagic Stroke - rupture
of a cerebral blood vessel
 Obstructive Stroke – occlusion
of a blood vessel
 Thrombus – blood clot that
forms within a blood vessel
 Embolus – piece of material
that forms in one part of the
vascular system, breaks off,
carried by blood stream until it
reaches a smaller artery
 Treatment
 Clot dissolving drugs
 Hypothermia
 Constraint-induced movement
therapy
Preview
 Tumors
 Seizure Disorders
 Cerebrovascular Accidents
 Disorders of Development
 Toxic chemicals
 Inherited metabolic disorders
 Down Syndrome
 Degenerative Disorders
 Disorders Caused by Infectious Diseases
Disorders of Development
 Toxic Chemicals
 During pregnancy, impairs fetal development
 Mother contracts rubella (German measles)
 Mother ingests alcohol during pregnancy
 Inherited Metabolic Disorders
 Phenylketonuria (PKU)
 Tay-Sachs disease
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
Down Syndrome
 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
Genetics of DS
 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
Down Syndrome
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
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 DISEASES
 PrPc (normal) and PrPsc (prion infected)
PrPC
PrPSC
PrPSC -protease-resistant (prion protein
also heat resistant)
 Abnormal protein taken up into neuron
by retrograde transport
Transmissible Spongiform Encephalopathies
 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
 APOPTOSIS: programmed
cell death
 Caspases: enzymes generated
by the cell initiating cell death
 BSE: caspase 12
Transmissable Spongiform
Encephalopathy
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
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
Degenerative Disorders
Lewy
Body
 Parkinson’s Disease
 A disease caused by degeneration of the nigrostriatal system – the
dopamine-secreting neurons of the substantia nigra (send axons to BG)
 Lewy Body – abnormal circular structures with a dense core consisting of
-synuclein protein (presynaptic protein); found in dopaminergic
nigrostriatal neurons of Parkinson’s patients.
DA pathways
Parkinson’s Disease
 1% of people over 65
 Symptoms:
 Muscular rigidity
 Slowness of movement
 Resting tremor
 Postural instability
 Difficulties with handwriting or making facial expressions
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
Toxic gain of function – genetic disorder caused by a dominant mutation that
involves a faulty gene that produces a protein with toxic effects
Genetic
causes of PD
 Mutation on chromosome 6produces 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
 Ubiquitination – targets the
abnormal proteins for
destruction by the proteasomes
 Kills the cell
Fig. 15.16
Sporadic PD
 ~95% of cases are sporadic (occur in the absence of
family history)
 Causes:
 Toxins present in environment
 Insecticides
 Faulty metabolism
 Unidentified infectious disorder
 Toxic chemicals inhibit mitochondrial functions which
leads to the aggregation of misfolded alpha-synuclein, in
DA neurons, kills the cell
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
 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
Treatment for PD
http://www.youtube.com/watch?v=d64iAcaK69M
MPTP – 1-methyl-4-phenyl-1,2,3-6-thrahydropyridine
 Nonhuman primates respond to MPTP the same as humans
 Cell loss in substantia nigra
 Level of DA is greatly reduced
 Gross motor symptoms
 Deprenyl (monamine agoinst) – blocks the effects of MPTP in the
animal model
 Inhibits the activity of the enyzme MAO-B
 Intracellular breakdown of DA by MAO-B causes the formation of H202 –
damages the cell
 Increases mitochondrial function in the brains of mice
 Administration in early Parkinson’s slows the progression of the disease
Treatment for PD
Stereotaxic surgery
 Transplantation of fetal tissue/neural stem cells
 Pallidotomies – surgical destruction of the internal
division of the globus pallidus
 Electric stimulation or lesion of subthalamic nucleus
 Genetically modified virus into the subthalamic
nucleus, delivered a gene for GAD (synthesis of
GABA)
 Causes some of the glutamate neurons into
GABA-producing neurons
 Symptoms improved
Treatment for PD
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
Treatment of PD
Transplantation of neural stem cells – undifferentiated
cells with potential to develop into DA neurons
 Transplantation of large number of cells – increasing
the numbers of surviving cells
 Remond et al., 2007
 MPTP injections in monkeys destroyed nigrostriatal 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
 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
Treatment of PD
Pallidotomies
 MRI to determine location of GPi
 low intensity, high-frequency
stimulation through electrode GPi,
temporarily disabling it
 If patients rigidity stopped (patient is
awake)
 Metabolic activity in premotor and
supplementary motor areas returns to
normal levels
 Release the motor cortex from inhibition
Treatment 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)
Treatment of PD
 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???
Gene Therapy as a Treatment of
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
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
Huntington’s Disease
 Degeneration of caudate nucleus and putamen
 Uncontrollable movements, jerky limb movements
 Progressive, cognitive and emotional changes
 Death (10-15 years)
HD
 The disease can affect both men and women.
 HD is 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.
 Physical symptoms of Huntington's disease can begin at any
age from infancy to old age, but usually begin between 35 and
44 years of age.
 About 6% of cases start before the age of 21 years with
an akinetic-rigid syndrome; they progress faster and vary
slightly.
Huntington’s Disease
 Neurodegeneration in the putamen
 First: Inhibitory neurons (GABAergic)
 Removes inhibitory control of motor areas in cortex
(hyperkinetic)
 As the disease progresses, neural degeneration occurs in many
other regions
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
Huntington’s Disease
 Normal Huntingtin (htt)
 Forms complex with
clatherin, Hip1 and AP2
 Involved in endocytosis
and neurotransmitter
release
 Huntington’s Disease
 Htt protein has abnormally
long glutamine tract
 May lead to abnormal
endocytosis and secretion
of neurotransmitters
Nature 415, 377-379 (2002)
 Striatal death by apoptosis  Another study: Li et al. 2000
 Caspase-3
 HD mice with caspase inhibitor lived longer
 Inhibits apoptosis
Huntington’s Disease
 Normal htt facilitates the production and transport of
brain derived neurotropic factor (BDNF)
 BDNF: neurotropic factor critical for the survival of neurons
 BDNF produced in cortex and transported to basal ganglia
 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
Huntington’s Disease
Fig. 15.20 (artist’s rendition):
Huntington’s Disease,
Inclusion Bodies
 Inclusion bodies:
 Role is unclear in Huntington’s Disease
 Tissue infected with abnormal htt produces inclusion bodies
 Neurons with inclusion bodies had lower levels of abnormal htt elsewhere
in the cell, cell lived longer than cells without inclusion bodies
 Neuroprotective?
Treatment of HD
 None
 Happ1 - Antibody that acts intracellularly (intrabody)
 Targets a portion of the Htt protein
 Mouse models of HD, insertion of the Happ1 gene into brain
suppressed production of mutant Htt and improved
symptoms
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
Alzheimer’s Disease
 Degenerative brain disorder of
unknown origin; causes progressive
memory loss, motor deficits, and
death.
 10% of the population over 65 years
old and 50% of the population over 85
 Severe degeneration of the
hippocampus, entorhinal cortex and
neocortex (prefrontal and temporal
association areas), Locus coeruleus,
Raphe nucleus
Signs of Alzheimer’s Disease
1.
Memory loss that disrupts daily life
2.
Challenges in planning or solving problems
3.
Difficulty completing familiar tasks at home, at work or at
leisure
4.
Confusion with time or place
5.
Trouble understanding visual images and spatial relationships
6.
New problems with words in speaking or writing
7.
Misplacing things and losing the ability to retrace steps
8.
Decreased or poor judgment
9.
Withdrawal from work or social activities
10. Changes in mood and personality
Alzheimer’s Disease
 Amyloid Plaque – Extracellular deposit containing a dense
core of -amyloid protein surrounded by degenerating
axons and dendrites and activated microglia and reactive
astrocytes.
Alzheimer’s Disease
 Neurofibrillary Tangle – a dying neuron containing intracellular
accumulations of abnormally phosphorylated tau-protein filaments that
formerly served as the cell’s internal skeleton.
 XS amounts of phosphate ions become attached to strands of tau, changing
its molecular structure
 Transport is disrupted, cell dies
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
Fig. 15.23
Alzheimer’s Disease
 Some forms of AD are familial
 APP gene – chromosome 21
 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.
 Netzer, W.J., Powell, C., Nong, Y., Blundell, J., Wong, L., Duff, K.,
Flajolet, M., Greengard, P. (2010). Lowering beta-amyloid levels
rescues learning and memory in a Down syndrome mouse
model. PLoS One. 5(6):e10943.
 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
 Other causes:
 Traumatic brain injury
Alzheimer’s Disease
 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
AD and protective effects of
“intellectual activity”
 The Religious Orders Study
 Positive relationship b/w increased number of years of formal
education and cognitive performance
 Billings et al., (2007)
 AD mice – contain mutant human gene for APP that leads
to development of AD
 Training on water maze every 3 months from age 2 and 18
months
 Training delayed the accumulation of Aβ and led to a
slowed decline of the animals’ performance
Treatment
 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
Preview
 Tumors
 Seizure Disorders
 Cerebrovascular Accidents
 Disorders of Development
 Degenerative Disorders





variant Creutzfeldt-Jackob (BSE)
Parkinson’s Disease
Huntington’s Disease
Alzheimer’s Disease
Multiple Sclerosis
Multiple Sclerosis
 Autoimmune demyelinating disease
 Sclerotic plaques
Multiple Sclerosis
 Epidemiology
 More women then men
 Late twenties-thirties
 Childhood in colder climates
 Canada has amongst the highest MS incidence estimates in the world
 55,000 – 75,000
 Prairie provinces and Atlantic Canada highest (2005; University of
Calgary)
Multiple Sclerosis
 TREATMENTS:
 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