Exam 2: Common Neurological Disorders

Question 1

Nervous System

What is the structure of the CNS?

Answer 1

Brain and spinal cord
Overall “command center”
Processing and integrating information

Question 2

Nervous System

What is the structure of the PNS?

Answer 2

Nerves and ganglia
Receives and projects information to and from the CNS
Mediates some reflexes

Question 3

Nervous System

What is the function of the motor nervous system?

Answer 3

Some CNS and PNS components - includes all axons that transmit nerve impulses from the CNS to a muscle or gland
Somatic
Autonomic

Question 4

Nervous System

Sensory Nervous System

Answer 4

Includes all axons that transmit impulses from a peripheral structure to the CNS (includes Eyes and Ears)
Somatic sensory
Visceral sensory

Question 5

Special Senses: Glaucoma

Pathogenesis of Glaucoma

Answer 5

Increased intraocular pressure
blocks blood flow through intraocular vessels (in the uvea)
Reduced blood flow deprives retina of nutrients (atrophy of retinal layer)

Question 6

Special Senses: Glaucoma

What causes increased intraocular pressure?

Answer 6

Increased production of vitreous humor
Decreased drainage of vitreous humor

Accumulation of vitreous humor

Question 7

Special Senses: Glaucoma

What causes atrophy of retinal layer?

Answer 7

reduced blood flow deprives retina of nutrients

Question 8

Special Senses: Glaucoma

What is the pathology of glaucoma?

Answer 8

Retinal Atrophy
* Disrupted nerve fiber layer (axon layer)
* Fewer cells in ganglion cell layer
* Damage to layer of rods and cones
* Overall thinning of retina

Plexiform laters are barely visible

Question 9

Special Senses: Glaucoma

What are the clinical symptoms of Glaucoma?

Answer 9

Retinal damage - blurred vision, impaired dark adaptation
Corenal damage - halos around lights
Optic Nerve Atrophy

Question 10

Special Senses: Ostosclerosis

Otosclerosis

Answer 10

Disease of the middle ear
Hardening of the tissue in the ear
May be asymptomatic
Genetic Component

Question 11

Special Senses: Ostosclerosis

What causes ostosclerosis?

Answer 11

Bony growth around oval window
* failure of resorption results in excess bone
* Immobilizes stapes (prevent vibration transmission)

Question 13

Special Senses: Ostosclerosis

What is the pathogenesis of Otosclerosis?

Answer 13

Starts with bone resorption
* uncoupling of resorption/deposition

Proceeds with fibrosis and vascularization of the temporal bone

Dense new bone replaces fibrotic tissue
* anchors the footplate of the stapes (cant vibrate againt oval window - deaf)

Question 14

Special Senses

Tinnitus

Answer 14

disease of the inner ear
ringining, hissing, whistling, humming, and/or roaring in the ears

Question 15

Special Senses: Tinnitus

Transient Tinnitus

Answer 15

not associated with disease
excessive stimulation of hair cells

Signalling hasnt stopped - usually goes away within a day or 2

Loud concert, club, loud party, etc.

Question 16

Special Senses

Persistent Tinnitus

Answer 16

Associated with hearing loss
associated with cochlear dysfunction or cranical nerve VIII dysfunction
hair cell damage w/hearing loss

Question 16

Diseases of the PNS

What are the types of PNS Diseases?

Answer 16

Neuromuscular
Myelin sheath

Question 17

PNS: Neuromuscular disease

Neuromuscular junctions

Answer 17

Terminals of motor axons synapse with sarcolemma
Neurotransmitter is acetylcholine

Question 18

PNS: Neuromuscular disease

Neurotransmitters

Answer 18

Can be excitatory or inhibitory
Usually amines, amino acids, or small peptides
Degraded in synaptic cleft, or taken up by endocytosis (prevent prolonged stimulation)
May act as paracrine hormones outside the nervous system

Question 19

PNS: Neuromuscular disease

How does Myasthenia gravis affect neuromuscular junctions?

Answer 19

Autoantibodies bind ACh receptors

Question 20

PNS: Neuromuscular disease

How does Botulism toxin affect neuromuscular junctions?

Answer 20

Directly effects ACh release

Question 21

PNS: Neuromuscular disease

How does Lambert-Eaton Syndrome affect neuromuscular junctions?

Answer 21

Attacks voltage-gated Ca2+ channels

Question 22

PNS: Neuromuscular disease: Myasthenia Gravis

Myasthenia Gravis

Answer 22

Antibody-mediated autoimmune disease
* Autoantibodies against ACh receptors (85% of patients)
* Induce aggregation and degredation of receptors (decreased number of receptors)

Reduced ACh receptors
* On post-synaptic membranes
* Reduced responsiveness to ACh - muscle weakness

Antibodies also interact with the thymus
* benign thymoma (10% of cases)
* Thymic Hyperplasia (30%)
* B-cell follicles in thymus

Question 23

PNS: Neuromuscular disease: Myasthenia Gravis

What are the clinical symptoms of Myasthenia Gravis?

Answer 23

Fluctuating weakness
* Increases over the course of the day
* increass upon exertion
* decreased muscle responsiveness upon repeated stimulation
Involvement of extra-ocular muscles

Question 24

# PNS: Neuromuscular disease: Myasthenia Gravis What is the treatment for Myasthenia Gravis?

Answer 24

Acetylcholinedterase inhibitors (ACh persists in synaptic cleft) Immunosuppressive therapy (glucocorticoids) or Plasmapheresis Thymectomy for patients with thymoma

Question 25

# PNS: Neuromuscular disease: Myelin Sheath Disease Myelin Sheath

Answer 25

Layers of membrane surround an axon In CNS, gives white matter its characteristic macroscopic appearance Function: important for signal transmisison Transmit signal through salatory conduction

Question 26

# PNS: Neuromuscular disease: Multiple Sclerosis Multiple Sclerosis

Answer 26

Myelin Sheath Disease Autoimmune demyelinating disorder - Both genetic and environmental components Lesions in myelin sheath reduce nerve transmission efficiency Relapsing episodes of neurologic deficits Freqiency increases with time, while recovery decreases Linked to MHC component (DR2) Also IL-2/IL-7 receptors

Question 27

# PNS: Neuromuscular disease: Multiple Sclerosis Describe the replasing episodes of multiple sclerosis

Answer 27

variable duration (weeks to years) gradual, partial recovery don't have full recovery episodes increase over time but recovery decreases

Question 28

# PNS: Neuromuscular disease: Multiple Sclerosis Why is MS an autoimmune disease?

Answer 28

Immune response to components of the myelin sheath Presence of chronic immune cells (especially T cells and macrophages) around myelin sheath plaques

Question 29

# PNS: Neuromuscular disease: Multiple Sclerosis What is the immune response of MS?

Answer 29

T helper cells initiate immune response against myelin antigens Cytokine release promotes macorphage and leukocyte infiltration Macrophages and leukocytes release agents to damage invaders agents damage myelin sheath indtead - b/c no invaders

Question 30

# PNS: Neuromuscular disease: Multiple Sclerosis Describe the tissue damage in MS

Answer 30

Consistent with other immune diseases Immune response itself produces tissue damage Lesions are firmer than surround tissue (sclerosis) ## Footnote Myelin is very soft - soft tissue gets replaces with harder tissue

Question 31

# PNS: Neuromuscular disease: Multiple Sclerosis What are common signs and symptoms of MS?

Answer 31

Unilateral visual impairment Brainstem involvement Spinal cord lesions

Question 32

# PNS: Neuromuscular disease: Multiple Sclerosis How is the brainstem involved in MS?

Answer 32

Cranial nerve signs ataxia nystagmus internuclear opthalmoplegia

Question 33

# PNS: Neuromuscular disease: Multiple Sclerosis What causes unilateral visual impairment?

Answer 33

Signal transmitted to axon as well only one eye

Question 34

# PNS: Neuromuscular disease: Multiple Sclerosis What causes/results from spinal cord lesions?

Answer 34

Cause: motor or sensory nerves (tingly) Spasticity and loss of bladder control | Signal in spinal cord is slow/glitchy

Question 35

# Diseases of the CNS Types of diseases of the CNS

Answer 35

Ethanol Toxicity Cerebrovascular Disease Prion Disease Motor Neuron diseases (degenerative) Degenerative Diseases Dementia (degenerative)

Question 36

# Diseases of the CNS: Ethanol Toxicity Toxic Nerve Damage

Answer 36

Cellular and tissue loss due to toxicity Carbon monoxide Methanol Ethanol Radiation

Question 37

# Diseases of the CNS: Ethanol Toxicity Toxic Nerve Damage: Unique considerations in the CNS

Answer 37

Isolation (BBB) - only toxins that can cross the BBB get into the CNS Meabolic needs repair capacity

Question 38

# Diseases of the CNS: Ethanol Toxicity Ethanol-induced toxicity

Answer 38

Acute abuse is generally reversible Chronic alcohol abuse associated with metabolic disturbances as well

Question 39

# Diseases of the CNS: Ethanol Toxicity What are the 3 mechanisms that cause CNS damage due to ethanol abuse?

Answer 39

Mostly associated with liver damage Hepatic encephalopathy - damage secondary to liver Thiamine deficiency Ethanol toxicity

Question 40

# Diseases of the CNS: Ethanol Toxicity Hepatic Encephalopathy

Answer 40

Glial response within the CNS (cerebral cortex and basal ganglia) Elevated ammonia and pro-inflammatory cytokines Astrocytes will be altered

Question 41

# Diseases of the CNS: Ethanol Toxicity How are astrocytes altered in hepatic encephalopathy?

Answer 41

Enlarged nuclei Minimal reactive cytoplasm

Question 42

# Diseases of the CNS: Ethanol Toxicity Thiamine Deficiency

Answer 42

Can be malnutrition or malabsorption Associated with chronic ethanol abuse

Question 43

# Diseases of the CNS: Ethanol Toxicity Acute Thiamine Deficiency | Wernicke Encephalopathy

Answer 43

Psychotic symptoms opthalmoplegia Reversible with thiamine supplementation

Question 44

# Diseases of the CNS: Ethanol Toxicity Chronic Thiamine Deficiency | Korsakoff Syndrome

Answer 44

Irreversible Short term memory problems Confabulation | Associated with lesions in the thalamus

Question 45

# Diseases of the CNS: Ethanol Toxicity What is the pathology of chronic thiamine deficiency?

Answer 45

Early - dilated capillaries with prominent endothelial cells Hemorrhagic/necrotic foci in ventricular walls of brain Eventual cyst formation

Question 46

# Diseases of the CNS: Ethanol Toxicity Ethanol Toxicity in CNS

Answer 46

Direct or secondary to malnutrition Cerebellar dysfunction in 1% of chronic alcoholics

Question 47

# Diseases of the CNS: Ethanol Toxicity What causes cerebellar dysfunction in chronic alcoholics?

Answer 47

Atrophy and loss of granule cells (intaneurons that transmit to purkinje cells) * excitatory signal from rest of nervous system * Participate in processing visual and motor information, as well as learning and memory

Question 48

# Diseases of the CNS: Ethanol Toxicity What are the clinical symptoms of Ethanol Toxicity?

Answer 48

Truncal ataxia Unsteady gate Nystagmus

Question 49

# Diseases of the CNS: Ethanol Toxicity What is the treatment for ethanol toxicity?

Answer 49

Get alocohol intake under control

Question 50

# Diseases of the CNS: Cerebrovascular Disease Cerebral Edema

Answer 50

Accumulation of excess fluid within brain parenchyma

Question 51

# Diseases of the CNS: Cerebrovascular Disease What causes cerebral edema?

Answer 51

Excess fluid leakage from blood vessels, or CNS cellular damage

Question 52

# Diseases of the CNS: Cerebrovascular Disease What are the 2 pathways for cerebral edema?

Answer 52

Vasogenic - BBB disruption and increased vascular permeability allow fluid to move from within vasculature to within parenchymal space Cytotoxic - Secondary to cell membrane injury (neuron, glia, endothelium)

Question 53

# Diseases of the CNS: Cerebrovascular Disease What causes cytotoxic cerebral edema?

Answer 53

Generalized hypoxia/ischemia Metabolic disruption - ionic homeostasis

Question 54

# Diseases of the CNS: Cerebrovascular Disease What is the pathology of cerebral edema?

Answer 54

Gyro flattened/sulci narrowed ventricles compressed if untreated can result in herniation

Question 55

# Diseases of the CNS: Cerebrovascular Disease What are the clinical symptoms of cerebral edema?

Answer 55

Range from subtle neurological deficits to death

Question 56

# Diseases of the CNS: Cerebrovascular Disease Focal Cerebral Ischemia

Answer 56

Limited to no blood flow to a specific area of brain Arterial occlusion or hypoperfusion

Question 57

# Diseases of the CNS: Cerebrovascular Disease What causes focal cerebral ischemia?

Answer 57

Embolism Vascular inflammation (hyperperfusion) In-situ thrombosis (atherosclerosis most frequently)

Question 58

# Diseases of the CNS: Cerebrovascular Disease What happens if focal cerebral ischemia is sustained?

Answer 58

Will develop cerebral infarct Size/location dependent on vessels involved and duration

Question 59

# Diseases of the CNS: Cerebrovascular Disease What is the immune response to focal cerebral ischemia?

Answer 59

1. neuronal stress (red neurons) 2. Macrophages and reactive gliosis to clean up damage 3. Repair - removal of tissue, loss of architechure, gliosis

Question 60

# Diseases of the CNS: Prion Diseases: Creutzfeldt-Jakob What are prions?

Answer 60

Abnormal forms of a cellular protein (specific protein called the Prion Protein (PrP)

Question 61

# Diseases of the CNS: Prion Diseases: Creutzfeldt-Jakob What do prions do?

Answer 61

Cause rapidly progressive neurodegenerative disorders: * sporadic, familial or transmitted * Creutzfeldt-Jakob disease, fatal familial insomnia, and kuru in humans * Scrapie in sheep and goats * Bovine spongiform encephalopathy (mad cow)

Question 62

# Diseases of the CNS: Prion Diseases: Creutzfeldt-Jakob What is the common pathology of prion diseases?

Answer 62

Spongiform change caused by intracellular vacuoles in neurons and glia

Question 63

# Diseases of the CNS: Prion Diseases: Creutzfeldt-Jakob What is the common clinical presentation of prion diseases?

Answer 63

rapidly progressive dementia

Question 64

# Diseases of the CNS: Prion Diseases: Creutzfeldt-Jakob How are prions formed?

Answer 64

PrP: 30 kD cytoplasmic protein present in neurons Conformational change: from its normal alpha-helix containing isoform (PRPc) to an abnormal beta-pleated sheet isoform (PRPsc)

Question 64

# Diseases of the CNS: Prion Diseases: Creutzfeldt-Jakob Spongiform Changes in Prion Diseases

Answer 64

Cerebral cortex Often, disease progresses so rapidly no noticeable atrophy is seen on gross examination of brain Average survival is 7 months

Question 65

# Diseases of the CNS: Prion Diseases: Creutzfeldt-Jakob What are the symptoms of prion diseases?

Answer 65

Changes in memory/behavior Dementia Startle myoclonus

Question 66

# Diseases of the CNS: Prion Diseases: Creutzfeldt-Jakob Bovine Spongiform Encephalopathy

Answer 66

Variant of CJD (no alteration in PrP gene) Caused by ingestion of prions from contaminated beef or blood transfusion damage in the cerebral cortex

Question 67

# Diseases of the CNS: Prion Diseases: Creutzfeldt-Jakob Kuru Plauqes

Answer 67

Extracellular aggrgated PrPsc Detectable with PAS or Congo red Usually found in the cerebellum not in cerebrum Also found inh vCJD

Question 68

# Diseases of the CNS: Motor Neuron Diseases: ALS Amyotrophic Lateral Sclerosis (ALD) | Lou Gehrig's Disease

Answer 68

Motor Neuron Disease Loss of lower motor neurons (spinal cord/brain stem) Loss of upper motor neurons (project into spinal cord) 5-10% are familial (90-95% are sporadic)

Question 69

# Diseases of the CNS: Motor Neuron Diseases: ALS What is the amyotrophic portion of ALS?

Answer 69

Muscular paralysis with absence of atrophy Also, hypertonia (rigidity) and exaggerated deep muscle tendon reflexes

Question 70

# Diseases of the CNS: Motor Neuron Diseases: ALS What is the lateral sclerosis portion of ALS?

Answer 70

Degeneration of corticospinal tracts Produces upper and lower motor neuron paralysis in the extremities

Question 71

# Diseases of the CNS: Motor Neuron Diseases: ALS Familial ALS

Answer 71

25% are gain of function mutation in copper-zinx superoxide dismutase (SOD1) Others: * Dynactin (retrograde transport) * VAMP-associated protein B (regulation of vesicle transport) * Alsin (has guanine nucleotide exchange factor domains; regulates endosomal trafficking)

Question 72

# Diseases of the CNS: Motor Neuron Diseases: ALS SOD1 and ALS

Answer 72

Impaired ability to eliminated ROS originally thought to kill neurons UPR induced by misfolded SOD1 is. now thought to be most likely mechanism May also contribute to malfunction of glial cells

Question 73

# Diseases of the CNS: Motor Neuron Diseases: ALS ALS Pathogenesis

Answer 73

SOD1 mutation Altered axonal transport Neurofilament abnormailites Glutamate toxicity (increases intracellular calcium) Development of protein aggregates (bunina bodies, PAS-binding inclusions in the cytoplasm) | Possible mechanisms

Question 74

# Diseases of the CNS: Motor Neuron Diseases: ALS Clinical Presentation of ALS

Answer 74

Loss of motor neurons/nerves * hand weakness * arm and leg spasiticity/cramping Eventually * Muscle strength and bulk decrease * fasciculations Death usually results from involvement of respiratory muscles (repeated infections)

Question 75

# Diseases of the CNS: Degenerative Diseases: Parkinson's Parkinson's disease

Answer 75

Degenerative disease Degeneration of the substantia nigra (SN) in the basal ganglia Tremor, rigidity, bradykinesia L-DOPA responsive

Question 76

# Diseases of the CNS: Degenerative Diseases: Parkinson's Parkinson's like diseases

Answer 76

associated with toxin or other cause e.g. a dopamine antagonist

Question 77

# Diseases of the CNS: Degenerative Diseases: Parkinson's Parkinson's Disease: SN pallor

Answer 77

Loss of pigmented neurons (B) Associated gliosis

Question 78

# Diseases of the CNS: Degenerative Diseases: Parkinson's Parkinson's Disease: Degeneration of neurons

Answer 78

Lack of dopamine

Question 79

# Diseases of the CNS: Degenerative Diseases: Parkinson's Parkinson's Disease: Lewy Bodies

Answer 79

Eosinophilic cytoplasmic inclusions alpha-synuclein fibers

Question 80

# Diseases of the CNS: Degenerative Diseases: Parkinson's α-synuclein

Answer 80

Lipid-binding protein associated with synapses mutation is associated with increased gene copy - gene dosage effect

Question 81

# Diseases of the CNS: Degenerative Diseases: Parkinson's overexpression of α-synuclein...

Answer 81

induces lewy body formation in mice inhibits melanin production in skin Activates melanin production in neurons | PD suspectibbility linked to melanoma incidence

Question 82

# Diseases of the CNS: Degenerative Diseases: Parkinson's Neuromelanin is linked to...

Answer 82

increased oxidative stress susceptibility in dopaminergic neurons

Question 83

# Diseases of the CNS: Degenerative Diseases: Parkinson's Molecular genetics of Familial PD: Associated gain of function mutations

Answer 83

Leucine-rich repeat kinase 2 (LRRK2) α-synuclein DJ-1 (redox stress response) PINK1 (kinase that regulates mitochondrial function)

Question 84

# Diseases of the CNS: Degenerative Diseases: Parkinson's Molecular genetics of Familial PD: Associated loss of function mutations

Answer 84

Parkin (associated with juvenile form)

Question 85

# Diseases of the CNS: Degenerative Diseases: Parkinson's What are the genetic suggested mechanisms of PD?

Answer 85

Stress response (UPR, ROS) - α-synuclein Defective proteasome function - parkin Altered mitochondrial function - DJ-1, PINK1

Question 86

# Diseases of the CNS: Degenerative Diseases: Parkinson's Parkinsonian Disorder: MPTP

Answer 86

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Byproduct of synthetic opioid production | Contaminanted street drugs

Question 87

# Diseases of the CNS: Degenerative Diseases: Parkinson's Parkinsonsian Disorder: MPTP: Mitochondrial toxin

Answer 87

Used to generate model systems for PD research Selectively injures dopaminergic neurons: * unknown mechanism for selectivity * However, dopamine exposure can increase ROS, so cells may be more sensitive to mitohcondrial damage

Question 88

# Diseases of the CNS: Degenerative Diseases: Parkinsonian Disorder MPTP Mechanism of Action

Answer 88

Converted to N-methyl-4-phenylpyridinium (MPP+) in astrocytes MPP+ inhibits complex I of the elctron transport chain Reduced ATP production and oxygen metabolism Increased ROS generation (Oxidative damage tolipids, proteins, nucleic acids

Question 89

# Diseases of the CNS: Degenerative Diseases: Parkinsonian Disorder What is the treatment for Parkinsonian Disorder: MPTP?

Answer 89

Remove exposure to toxin

Question 90

# Diseases of the CNS: Dementia: Alzeherimer Disease Dementia

Answer 90

Impairment of memory and other cortical function, while alertness is preserved

Question 91

# Diseases of the CNS: Dementia: Alzeherimer Disease Demetia: Alzheimer Disease

Answer 91

Most common cause of dementia (>50%) 5-10 year disease course First sign is impaired learning and recall of recent memories

Question 92

# Diseases of the CNS: Dementia: Alzeherimer Disease What is the pathogensis of Alzheimer Disease?

Answer 92

Presence of specific amyloid plaques (extracellular, found in cerebral cortex and blood vessel walls(meningeal and cerebral)) Formation of neurofibrillary tanflws (NFTs) Includes neuron and synaptic loss, as well as the presence of reactive astrocytosis and microglial proliferation

Question 93

# Diseases of the CNS: Dementia: Alzeherimer Disease Reactive astrocytosis

Answer 93

Increased size and number of astrocytes un response to traumatic injury Synthesis and release of cytokines Induce migration of immune cells into CNS Astrocytes also remove excessive glutamate through specific transporters to prevent glutamate cytotoxicity

Question 94

# Diseases of the CNS: Dementia: Alzeherimer Disease Neurofibrillary tangles

Answer 94

No specific for AD Paired helical filaments containing hyperphosphorylated tau Also found in neuron processes (neurites) surrounding plaques

Question 95

# Diseases of the CNS: Dementia: Alzeherimer Disease Extracellular plaques | neuritic plaques

Answer 95

Central amyloid β core with 'halo' Surrounded by network of misshapen neuron processes Microglia and reactive astrocytes at periphery (immune response)

Question 96

# Diseases of the CNS: Dementia: Alzeherimer Disease Proteins associated with AD: Presenilins

Answer 96

Subunits of γ-secretase Important for proper amyloid processing, as well as other subtrates critical for neuron function

Question 98

# Diseases of the CNS: Dementia: Alzeherimer Disease Proteins associated with AD: Apolipoprotein E4

Answer 98

Mediates LDL binding to receptor Promoted Aβ formation and deposition, possibly through binding ApoE3 binds tau (prevents aggregation?)

Question 99

# Diseases of the CNS: Dementia: Alzeherimer Disease Proteins associated with AD

Answer 99

Presenilins Apolipoprotein E4 Amyloid β

Question 100

# Diseases of the CNS: Dementia: Alzeherimer Disease Aβ - induced neuronal damage

Answer 100

Directly cytotoxic * number of plaques does not correlate well to disease Synaptic dysfunction * block long-term potentiation, other membrane changes Inflammatory response * mediators induce localized damage * affect tau phosphorylation * cause oxidative damage

Question 101

# Diseases of the CNS: Dementia: Alzeherimer Disease What are some consequences of neuronal loss?

Answer 101

Loss of: Speech Reading/writing language comprehension