Chapter 23: Diseases of Myelin and Neurodegenerative Diseases

Question 1

Axons are tightly ensheathed by myelin. What is the function of myelin?

Answer 1

Electrical insulator that allows rapid propagation of neural impulses

Question 2

Why are diseases of myelin primarily white matter disorders

Answer 2

because although myelinated axons are present in all areas of the brain, they are the dominant component in the white matter

Question 3

Fill in: oligodendrocytes/schwann cells make myelin in the brain

Answer 3

oligodendrocytes

Question 4

In general, CNS diseases involving myelin are separated into two broad groups. Which two? (+explain a little)

Answer 4

• Demyelinating diseases of the CNS are acquired conditions characterized by preferential damage to previously normal myelin. The most common diseases in this group result from immune-mediated injury (e.g. MS), viral infection of oligodendrocytes (e.g. PML), and injury caused by drugs and other toxic agents.
• By contrast, in other diseases, myelin is not formed properly or has abnormal turnover kinetics, caused by mutations. These diseases are grouped under leukodystrophy or dysmyelinating diseases.

Question 5

What is Multiple Sclerosis (MS)?

Answer 5

MS is an autoimmune demyelinating disorder characterized by episodes of disease activity, separated in time, that produce white matter lesions that are separated in space. It is the most common demyelinating disorder.

Question 6

What are the lesions of MS caused by?

Answer 6

An autoimmune response directed against components of the myelin sheath

Question 7

Immune mechanisms that underlie the destruction of myelin are the focus of much investigation. What are some (recent) research outcomes?

(this is for your own understanding, just read this 1-2x)

Answer 7

The available evidence indicates that the disease is initiated by TH1 and TH17 T cells that react against myelin antigens and secrete cytokines. Experimental autoimmune encephalomyelitis, an animal model of MS in which demyelination and inflammation occur after immunization of animals with myelin proteins, can be passively transferred to unimmunized animals with TH1 and TH17 cells that recognize myelin antigens. TH1 cells secrete IFN-γ, which activates macrophages, and TH17 cells promote the recruitment of leukocytes. The demyelination is caused by activated leukocytes and their injurious products. The infiltrate in plaques and surrounding regions of the brain consists of T cells (mainly CD4+, some CD8+) and macrophages. B lymphocytes and antibodies also play an important, but poorly defined, role in the disease, as indicated by the surprising success of B cell depleting therapies.

Question 8

How can you recognize MS in a patient?

Answer 8

Multiple relapses followed by episodes of remission (with incomplete recovery). Over time gradual/stepwise accumulation of neurologic deficits occur

Question 9

What does the CSF of patients with MS show?

Answer 9

A mildly elevated protein level with an increased proportion of immunoglobulin; in one-third of cases, there is moderate pleocytosis. When the immunoglobulin is examined further, oligoclonal bands usually are identified. These antibodies are directed against a variety of antigenic targets and can be used as markers of disease activity. The contribution of these antibodies to the disease process is unclear.

Question 10

Immune-mediated demyelination can occur after a number of systemic infectious illnesses. Such as which?

Answer 10

relatively mild viral diseases

Question 11

True/false: Immune-mediated demyelination as a consequence of systemic infectious illnesses can be related to direct spread of the infectious agents to the nervous system.

Answer 11

False, rather, it is believed that immune cells responding to pathogen-associated antigens cross-react against myelin antigens, resulting in myelin damage.

Question 12

True/false: Postinfectious auto-immune reactions to myelin are associated with acute-onset monophonic illness

Answer 12

True

Question 13

Other acquired diseases of myelin include neuromyelitis optica (NMO), central pontine myelinolysis and progressive multifocal leukoencephalopathy. What are they?

(only PML is discussed in the lecture)

Answer 13

• Neuromyelitis optica (NMO), an antibody-mediated demyelinating disease centered on the optic nerves and spinal cord,
• Central pontine myelinolysis, caused by nonimmune damage to oligodendrocytes typically after sudden correction of hyponatremia, that may result in a rapidly evolving quadriplegia.
• Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease that occurs after reactivation of the JC virus in immunosuppressed patients.

Question 14

What are leukodystrophies? (+what are they caused by)

Answer 14

Leukodystrophies are inherited dysmyelinating diseases caused by abnormal myelin synthesis or turnover. They are caused by mutations of genes whose products are involved in the generation, turnover, or maintenance of myelin

Question 15

What symptoms do patients with a leukodystrophy present with?

Answer 15

There is typically diffuse involvement of white matter leading to deterioration in motor skills, spasticity, hypotonia, or ataxia

Question 16

How can you distinguish between leukodystrophy and demyelinating diseases?

Answer 16

The leukodystrophies typically present with an insidious and progressive loss of function, often begin at younger ages, and are associated with diffuse and symmetric changes on imaging studies.

Question 17

What are neurodegenerative diseases characterized by?

Answer 17

The progressive loss of neurons, typically affecting groups of neurons with functional interconnections.

Question 18

Why do neurodegenerative diseases have relatively stereotypic presenting signs and symptoms?

Answer 18

Different diseases tend to involve particular neural systems

Question 19

How do diseases that involve the hipoocampus and associated cortices present?

(+ name example)

Answer 19

With cognitive changes, often including disturbances of memory, behavior, and language. With time these progress to dementia, as occurs with Alzheimer disease

Question 20

How do diseases that affect the basal ganglia manifest?

+ name example

Answer 20

As movement disorders; these may be hypo kinetic, as with Parkinson disease, or hyperkinetic, as with Huntington disease

Question 21

How do diseases that involve the cerebellum or its input and output circuitry present?

(+ name example)

Answer 21

Ataxia, as seen in the spinocerebellar ataxias

Question 22

How do diseases that involve the motor system present?

+ name example

Answer 22

Weakness and difficulty with swallowing and respiration are often seen first, as with amyotrophic lateral sclerosis.

Question 23

What pathologic process is shared by most neurodegenerative diseases?

Answer 23

Accumulation of protein aggregates, which serve as histologic hallmarks of specific disorders

Question 24

What are the clinical pattern(s) and protein inclusion(s) of Alzheimers disease (AD)?

Answer 24

Clinical pattern: dementia

Protein inclusions: Aß (plaques) and Tau (tangles)

Question 25

What are the clinical pattern(s) and protein inclusion(s) of Frontotemporal lobar degeneration (FTLD)?

Answer 25

Clinical pattern: Behavioral changes, language
disturbance
Protein inclusions: Tau,
TDP43 and others (rare)

Question 26

What are the clinical pattern(s) and protein inclusion(s) of Parkinson disease (PD)?

Answer 26

Clinical pattern: Hypokinetic movement disorder

Protein inclusions: α-synuclein and Tau

Question 27

What are the clinical pattern(s) and protein inclusion(s) of Huntington disease (HD)?

Answer 27

Clinical pattern: Hyperkinetic movement disorder

Protein inclusions: Huntingtin (polyglutamine repeat expansions)

Question 28

What are the clinical pattern(s) and protein inclusion(s) of spinocerebellar ataxias?

Answer 28

Clinical pattern: Cerebellar ataxia

Protein inclusions: Various proteins (polyglutamine repeat expansions)

Question 29

What are the clinical pattern(s) and protein inclusion(s) of Amyotrophic lateral sclerosis (ALS)?

Answer 29

Clinical pattern: Weakness with upper and lower motor neurons signs
Protein inclusions: SOD I and TDP43

Question 30

How can aggregates arise?

Answer 30

• Mutations that alter the protein’s conformation or disrupt pathways involved in processing or clearance of the proteins
• Subtle imbalance between protein synthesis and clearance (due to genetic, environmental or stochastic factors)

Question 31

True/false: Aggregates can seed the development of more aggregates, and the disease process can spread

Answer 31

Surprisingly, yes. (e.g. Prion)

Question 32

Explain the process/clinical presentations of AD?

I know I’ve asked this before, but try to be more detailed

Answer 32

The disease usually manifests with the insidious onset of impaired higher intellectual function, memory impairment, and altered mood and behavior. Over time, disorientation and aphasia, findings indicative of severe cortical dysfunction, often develop; those in the final phases of AD are profoundly disabled, often mute and immobile. Death usually occurs from intercurrent pneumonia or other infections.

Question 33

What is the pathogenesis of AD?

I know I’ve asked this before, but try to be more detailed

Answer 33

The fundamental abnormality in AD is the accumulation of two proteins (Aβ and tau) in specific brain regions, in the forms of plaques and tangles, respectively; these changes result in secondary effects including neuronal dysfunction, neuronal death, and inflammatory reactions. Plaques are deposits of aggregated Aβ peptides in the neuropil, while tangles are aggregates of the microtubule binding protein tau, which develop intracellularly and then persist extracellularly after neuronal death

Question 34

What is the pathogenesis of AD in key points? (the details of how these play a role you don’t have to learn for the exam)

Answer 34

Aß, Tau, genetic factors, inflammation

Question 35

Amyloid precursor protein can be cleaved by ß-Secretase, a-Secretase and y-Secretase. Which results in aggregation of amyloid-beta?

Answer 35

ß-Secretase

Question 36

How will an Aß-monomer cause plaques tangles? (like, what are the steps)

Answer 36

Aß monomer -> Aß oligomers -> Aßaggregates -> Amyloidfibrils -> Plaques and tangles (from this point, Tau is also integrated in the proces)

Question 37

What is a neuritic plaque, and what is a neurofibrillary tangle? (in simple words)

Answer 37

Neuritic plaque: extracellular lesion

Neurofibrillary tangle: intracellular lesion

Question 38

What are neuritic plaques (in more detail)?

just read this 1-2x, don’t learn pls

Answer 38

Neuritic plaques are focal, spherical collections of dilated, tortuous, processes derived from dystrophic neurites, often around a central amyloid core. Neuritic plaques range in size from 20 to 200 μm in diameter; microglial cells and reactive astrocytes are present at their periphery. Plaques can be found in the hippocampus and amygdala as well as in the neocortex, although there is relative sparing of primary motor and sensory cortices until late in the disease course. The amyloid core contains Aβ. Aβ deposits also can be found that lack the surrounding neuritic reaction, termed diffuse plaques; these are found in the superficial cerebral cortex, the basal ganglia, and the cerebellar cortex and may represent an early stage of plaque development.

Question 39

What are neurofibrillary tangles (in more detail)?

just read this 1-2x, don’t learn pls

Answer 39

Neurofibrillary tangles are bundles of paired helical filaments visible as basophilic fibrillary structures in the cytoplasm of the neurons that displace or encircle the nucleus; tangles can persist after neurons die, becoming a form of extracellular pathology. They are commonly found in cortical neurons, especially in the entorhinal cortex, as well as in the pyramidal cells of the hippocampus, the amygdala, the basal forebrain, and the raphe nuclei. A major component of paired helical filaments is hyperphosphorylated tau

Question 40

What is Frontotemporal local degeneration (FTLD) and what are the symptoms?

Answer 40

Frontotemporal lobar degeneration (FTLD) encompasses several disorders that preferentially affect the frontal and/ or temporal lobes. As a result, these disorders have certain shared clinical features, such as progressive deterioration of language and changes in personality

Question 41

How can FTLD be distinguished from AD?

Answer 41

In general, behavioral and language problems precede memory disturbances, a distinction that assists in the clinical discrimination between FTLD and AD. The onset of symptoms occurs at younger ages for FTLD than for AD.

Question 42

True/false: Pick’s disease is a form of FTLD

Answer 42

True

Question 43

What aggregates are formed in FTLD?

Answer 43

The DNA/RNA-binding protein TDP43 (FTDL-TDP43)

Question 44

How is Parkinson disease (PD) characterized?

Answer 44

Parkinson disease (PD) is a neurodegenerative disease marked by a hypokinetic movement disorder that is caused by loss of dopaminergic neurons from the substantia nigra. Parkinsonism is a clinical syndrome characterized by tremor, rigidity, bradykinesia, and instability

Question 45

What is the pathogenesis of PD?

Answer 45

PD is associated with protein accumulation and aggregation, mitochondrial abnormalities, and neuronal loss in the substantia nigra and elsewhere in the brain

Question 46

Which protein aggregates in PD, forming what?

Answer 46

A-synuclein forming Lewy bodies

Question 47

Are there genetic relations to PD?

Answer 47

Yes, although mostly sporadic, some point mutations and duplications can cause autosomal dominant PD

Question 48

How is PD treated?

Answer 48

L-DOPA (until a certain extend) deep brain stimulation

Question 49

How is it called when dementia arises within 1 year of onset of motor symptoms?

Answer 49

Lewy body dementia (LBD)

Question 50

What is Huntington disease (HD)? (+symptoms)

Answer 50

Huntington disease (HD) is an autosomal dominant movement disorder associated with degeneration of the striatum (caudate and putamen). The disorder is characterized by involuntary jerky movements of all parts of the body; writhing movements of the extremities are typical.

Question 51

What is the pathogenesis of HD?

Answer 51

HD is caused by CAG trinucleotide repeat expansions in a gene located on 4p16.3 that encodes the protein huntingtin. Normal alleles contain 11 to 34 copies of the repeat; in disease-causing alleles, the number of repeats is increased, sometimes into the hundreds. There is a strong genotype-phenotype correlation, with larger numbers of repeats resulting in earlier-onset disease.

Question 52

What are spinocerebellar ataxias (SCSs)?

Answer 52

Spinocerebellar ataxias (SCAs) are a heterogeneous group of several dozen diseases with clinical findings that include a combination of cerebellar and sensory ataxia, spasticity, and sensorimotor peripheral neuropathy

Question 53

What is amyotrophic lateral sclerosis (ALS)? (+ symptoms)

Answer 53

Amyotrophic lateral sclerosis (ALS) results from the death of lower motor neurons in the spinal cord and brain stem as well as upper motor neurons (Betz cells) in the motor cortex. The loss of lower motor neurons results in denervation of muscles, muscular atrophy (the “amyotrophy” of the condition), weakness, and fasciculations, while the loss of upper motor neurons results in paresis, hyperreflexia, and spasticity, along with a Babinski sign. An additional consequence of upper motor neuron loss is degeneration of the corticospinal tracts in the lateral portion of the spinal cord (“lateral sclerosis”). Sensation usually is unaffected, but cognitive impairment is not infrequent.

Question 54

Is there a genetic link for ALS?

Answer 54

Yes, such as mutations in superoxide dismutase gene (SOD1), but also many other genetic loci

(I don’t think you ought to know all of them)