Neurodegenerative demyelinating diseases (Gianani)

Question 1

Dementia (loss of mental power) is a generic term, not a disease entity. Any pathology that causes significant brain damage, at any age, can cause dementia. The causes of dementia include:

Answer 1

Stroke and ischemic encephalopathy (multi-infarct or vascular dementia)

Hippocampal sclerosis

Head trauma (subdural hematomas, diffuse axonal injury, chronic traumatic encephalopathy)

Hydrocephalus

CNS infections (HIV encephalitis, Creutzfeldt-Jakob disease)

Metabolic CNS disorders (lysosomal storage and peroxisomal diseases)

Demyelinative diseases (multiple sclerosis)

Neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, diffuse Lewy body dementia, Huntington’s disease, and others)

Neuropsychiatric disorders

Severe medical illness or organ failure
The effects of medications

Question 2

Cortical -

Answer 2

• Alzheimer’s disease
• Frontotemporal dementias ,Pick’s disease
• Diffuse Lewy body disease
• Corticobasal degeneration

Question 3

Midbrain

Answer 3

• ** Parkinson’s disease
  • Idiopathic
• Post-infectious
• Toxic (Meperidine analog MTPT)
• Parkinsonian dementia complex of Guam
• Multiple system atrophy (Striatonigral degeneration; Olivoponto- cerebellar degeneration; Shy Drager S.)
  
  • Progressive supranuclear palsy (PSP)

Question 4

Caudate nucleus

Answer 4

Huntington’s disease

Question 5

Spinocerebellar degenerations

Answer 5

(CAG repeat syndromes)

• Spinocerebellar ataxias
• Friedreich’s ataxia

Question 6

Motor system

Answer 6

(Upper cerebral cortex and lower motor neurons in brain stem and spinal cord )- Amyotrophic lateral sclerosis
- Spinomuscular atrophy

Question 7

Mechanisms of cellular damage

Answer 7

Free radicals with oxidative injury
DNA damage & repair
Excitotoxicity
Blood brain barrier dysfunction
Mitochondrial dysfunction with energy depletion
*** Protein truncation with dysfunction/misfolding and/or accumulation

Question 8

Liver: α1-Antitrypsin Deficiency

Answer 8

Just a reminder…..another disease caused by protein misfolding
This is not apoptosis! This is the actual misfolded protein in the cytoplasm. This leads to apoptosis…inflammation…cirrhosis..

Question 9

Protein Misfolding and Aggregation (mainly know the list of proteins)

Answer 9

Common feature of several neurodegenerative conditions:

Beta-Amyloid: Alzheimer Disease (AD), *Cerebral Amyloid Angiopathy

Tau (tauopathies): AD*, Frontotemporal Lobar Degeneration (FTLD), Picks Disease, Progressive Supranuclear Palsy, Corticobasal Degeneration

TDP43: Frontotemporal Lobar Degeneration (FTLD), some forms of ALS

Synuclein (synucleinopathies): Parkinson’s *Disease, Dementia with Lewy Bodies Disease, Multiple System Atrophy

Huntingtin: Huntington Disease

Prion protein( PrP ): CJD, vCJD, GSS, FFI

Question 10

Prions or prion type of behavior of proteins in

neurodegenerative disorders

Answer 10

“This capacity for a protein in an abnormal conformation to induce similar structural change in other molecules as a self-propagating process has recently been demonstrated for many of the aggregating proteins associated with traditional neurodegenerative diseases. The suggestion that, at least within an individual, there may be cell-to-cell spread of disease-associated protein aggregates provides a link between prion diseases and other disorders such as Alzheimer disease and Parkinson disease.”

Question 11

Alzheimer Disease

Answer 11

Tau and β-amyloid

Most common dementia (~85%)
Onset >65 years of age
Slowly progressive memory dysfunction
Dysphasia, dyspraxia
Progression to akynetic mutism
Most are sporadic
A minority are familial (earlier onset)
Down syndrome

Question 12

alzheimer’s Signs and Symptoms

Answer 12

Progressive memory loss 
Poor planning and problem solving
Confusion with time and place
Problems with word finding
Misplacing objects
Decreasing judgment
Social withdrawal
Mood/personality changes

Question 13

Genetics of Familial AD

Answer 13

Familial: Mutations of……..
β amyloid precursor protein (21q21)
In the Down syndrome region

Early onset: mutations of...
Presenilin 1 (14q24.3)
Presenilin 2 (1q31-q42)

Mutation of any of the above genes leads to increased β- amyloid precursor protein

Apolipoprotein E gene (19q13.2) (ε4 isoform) increases risk about 25% for late onset AD
(This apoE isoform promotes β-amyloid precursor protein formation)
Tau (17q21.1)

Question 14

main things to know about alzheimer’s

Answer 14

Tau
neurofibrillary tangles

High levels of tau protein in the CSF linked to poor recovery after head trauma

Inflammatory reaction to amyloid plaques and Tau tangles, with subsequent gliosis leads to grey matter loss.

Question 15

CEREBRAL AMYLOID ANGIOPATHY

Answer 15

This is not Alzheimer Disease but when AD is present this condition is almost always present !

The ischemic lesions of CAA cause dementia.

Can cause ischemic or hemorrhagic lesions….vessel lumen can obliterate…vessel wall becomes weak and can break.

Question 16

PICK’S DISEASE

Answer 16

Described almost 2 decades before AD.
Pick’s disease has long been the prototype of FTLDs.

It presents between 45-65 years with confusion and FTLD
symptoms and has a progressive course lasting 2-5 years, sometimes more.

In advanced stages it cannot be distinguished clinically from AD.

• The brain shows atrophy of frontal and temporal lobes,

** Pick bodies (tau-positive spherical cytoplasmic neuronal inclusions)

Question 17

AD: plaques composed of

Answer 17

dystrophic neurites
beta amyloid
tau

Question 18

AD: tangles composed of

Answer 18

tau

both intracellular and extracellular

Question 19

Progressive supranuclear palsy

(not important)

Answer 19

PSP is a tauopathy in that affected individuals commonly develop progressive truncal rigidity, disequilibrium with frequent falls and difficulty with voluntary eye movements.

Other symptoms that are frequently observed include nuchal dystonia, pseudobulbar palsy and a mild progressive dementia.

The onset is usually between the fifth and seventh decades, with males affected approximately twice as frequently as females.
The disease is often fatal within 5 to 7 years of onset.

Question 20

Parkinson Disease (PD)

Answer 20

Presents as a hypokinetic movement disorder caused by loss of dopaminergic neurons from the substantia nigra (nigrostriatal system)
Progresses as a global neurodegenerative disease to involve the cerebral cortex frequently leading to cognitive impairment… “Dementia with Lewy Bodies”.
The dopaminergic neurons of the substantia nigra project to the striatum and results in depletion of striatal dopamine.
The severity of the motor syndrome is proportional to the dopamine deficiency.

Question 21

Etiology of Parkinson Disease

Answer 21

IDIOPATHIC form……..Unknown

MPTP PARKINSONISM

GUAM PARKINSON-DEMENTIA (GPD)
- toxic amino acid in the seed of a cycad plant which is used to make flour and is a staple in the local diet

Aluminum
- Aluminum can disrupt the neuronal cytoskeleton and cause neurofibrillary pathology.

Parkinsonian syndromes may also develop in the course of other conditions that damage the SN, e.g., striatonigral degeneration, postencephalitic parkinsonism, manganese poisoning, carbon monoxide poisoning, hypoxic-ischemic encephalopathy, traumatic brain injury, and stroke.

Question 22

basal ganglia info

Answer 22

Virtually all inputs to the basal ganglia arrive via the striatum (caudate, putamen, and nucleus accumbens). Outputs leave the basal ganglia via the internal segment of the globus pallidus and the closely related substantia nigra pars reticulata and compacta.

Question 23

The presumptive diagnosis of PD

Answer 23

can be based on the presence of the central triad of parkinsonism—tremor, rigidity, and bradykinesia—in the absence of a toxic or other known underlying etiology.

The clinical syndrome of parkinsonism combines:

diminished facial expression (often termed masked facies)
stooped posture
slowing of voluntary movement
festinating gait (progressively shortened, accelerated steps)
rigidity
“pill-rolling” tremor

This impression is confirmed by symptomatic response to l-DOPA replacement therapy.

Question 24

Deep brain stimulation (DBS

Answer 24

In DBS, electrodes implanted into the subthalamic nucleus or inner part of the globus pallidus provide electrical stimulation to these and surrounding structures. This stimulation induces physiological and chemical changes that ameliorate some of the motor symptoms of PD by a poorly understood mechanism. Unilateral tremor and rigidity may also respond to stereotactic ablation of the contralateral globus pallidus, ventrolateral thalamus, or subthalamic nucleus.

Question 25

pathogenesis of parkinsonism

Answer 25

PD is a synucleinopathy.

Fibrils made of insoluble polymers of alpha synuclein are deposited in the neuronal body, forming round lamellated eosinophilic cytoplasmic inclusions, the Lewy bodies (LBs).

Alpha synuclein is also deposited in neuronal processes (Lewy neurites), and in astrocytes and oligodendroglial cells.

LBs cause neuronal degeneration and death.

LBs are ultimately found throughout the brain.

** Like Aβ in AD, α-synuclein has been shown to form aggregates.

Question 26

result of lewy bodies

Answer 26

LBs cause neuronal degeneration and death.

PD is a synucleinopathy. Fibrils made of insoluble polymers of alpha synuclein are deposited in the neuronal body, forming round lamellated eosinophilic cytoplasmic inclusions, the Lewy bodies (LBs).

Question 27

DIFFUSE LEWY BODY DISEASE

Answer 27

Diffuse Lewy body disease (DLBD) (Lewy body dementia) is a sporadic neurodegenerative disease, which is thought to be the second most common cause of dementia after AD.

It combines the neurological manifestations of dementia and parkinsonism.

Unlike AD in which short term memory is affected early, patients with DLBD present with fluctuating attention and cognition and visual hallucinations.

Motor parkinsonian manifestations (bradykinesia, rigidity, and less frequently tremor) vary in severity and may appear later.

DLBD patients have also depression, sleep disorder, and autonomic dysfunction.

The brain in DLBD is not as atrophic as it is in AD, and shows small, inconspicuous Lewy bodies in the neocotex, limbic system, and brainstem.

A large proportion of DLBD patients also have AD pathology.

Question 28

Multiple System Atrophy (not important)

Answer 28

The “multiple” in the term multiple system atrophy refers to three distinct neuroanatomic circuits that are commonly involved:

1) the striatonigral circuit (leading to parkinsonism),
2) olivopontocerebellar circuit (leading to ataxia), and
3) the autonomic nervous system including the central elements (leading to autonomic dysfunction, with orthostatic hypotension as a prominent component).

There are no Lewy bodies in the substantia nigra. A key feature of the pathology is the presence of filamentous
α- synuclein - immunoreactive cytoplasmic inclusions in oligodendrocytes.

Question 29

Huntington Disease

Answer 29

• fatal autosomal dominant condition that begins
• usually in the 4th to 5th decade
• characterized by behavioral changes, chorea, and dementia.
• rarely, symptoms begin before age 20.
• inclusions: abnormal huntingtin protein (combined with ubiquitin)
• emerging evidence: aggregated huntingtin can be taken up by neurons, prion-like spread from one neuron to another?

Question 30

The gene for HD

Answer 30

HTT, located on chromosome 4p16.3, encodes a 348-kD protein known as huntingtin. In the first exon of the gene there is a stretch of CAG repeats that encodes a polyglutamine region near the N terminus of the protein. Normal HTT genes contain six to 35 copies of the repeat; when the number of repeats is increased beyond this level it is associated with disease.

In HD, repeat expansions occur during spermatogenesis, so that paternal transmission is associated with early onset in the next generation, a phenomenon termed anticipation.

Question 31

If there are more than 36 CAG repeats =

Answer 31

“Repeat expansion” = HD

4p16.3

–> abnormally long string of glutamines

Question 32

Trinucleotide repeat distorders

There are three key mechanisms by which unstable repeats cause diseases:

Answer 32

(1) Loss of function of the affected gene, typically by transcription silencing, as in fragile X syndrome. In such cases the repeats are generally in non-coding part of the gene

***(2) A toxic gain of function by alterations of protein structure as in Huntington disease and spinocerebellar ataxias. In such cases the expansions occur in the coding regions of the genes.

(3) A toxic gain of function mediated by mRNA as is seen in fragile X tremor-ataxia syndrome.

Question 33

Huntington’s- destruction of

Answer 33

the caudate

What residual tissue is left behind after the caudate is destroyed is replaced by gliosis…glial cells stain GFAP +

Question 34

Huntington’s Disease etiology, manifestations, treatment

Answer 34

Etiology:

• Autosomal doinant progressive chorea and dementia
• Defective huntingtin protein (chromosome 4)
• degeneration of cholinergic and GABA-ergic cells in BG
• relative excess of dopamine

Manifestations:
middle age onset
chorea
violent outbursts, psychosis, withdrawal

Treatment:
dopamine antagonists
genetic screening

Question 35

cortex involvement in basal ganglia movement disorders

Answer 35

parkinson- hypoactive cortex
Huntington- hyperactive cortex
hemiballismus- hyperactive cortex

Question 36

Amyotrophic Lateral Sclerosis (ALS)

Answer 36

Is a fatal degenerative disorder of upper and lower motor neurons. *

Lower motor neuron loss causes muscle weakness, atrophy, and fasciculations;

upper motor neuron involvement causes spasticity, clonus, hyperactive tendon reflexes, and Babinski signs.

• Dementia appears at the onset or develops later in a significant proportion of ALS patients.

In about 25% of cases, ALS begins with brainstem symptoms (dysarthria, difficulty swallowing) followed by extremity weakness. This variant is called progressive bulbar palsy and has a worse prognosis.

• ALS is relentlessly progressive. The majority of patients die, usually from respiratory paralysis, within 2-3 years from the onset of symptoms.

There is no specific diagnostic test for ALS. The diagnosis is based on a combination of clinical and electrodiagnostic findings and muscle biopsy results.

Question 37

ATAXIA AND CEREBELLAR DEGENERATION

not discussed by Gianani

Answer 37

In terms of genetics, ataxias can be divided into 3 groups listed below:

Friedreich’s ataxia (FRDA)-an autosomal recessive ataxia caused by GAA repeats on the frataxin gene. Ataxia, spasticity, weakness, sensory neuropathy, cardiomyopathy. 1st decade…hand clumsiness, gait ataxia, pes cavus, diabetes(25%)…death usually because of CHF/arrythmias

Spinocerebellar ataxias(SCA)-a group of autosomal dominant ataxias (25 entities at last count), caused by CAG repeats on multiple chromosomal loci

Cerebellar ataxias-a diverse group of sporadic diseases that cause cerebellar degeneration and degeneration of other anatomical systems

In addition to the inherited ataxias, cerebellar degeneration is caused by a variety of acquired conditions including prion disease, HIE, nutritional deficiency, and inherited metabolic diseases.

Question 38

Friedrich’s ataxia

Answer 38

degenerative disease, not demyelinating

Loss of sensory ganglion cells and degeneration of their axons in peripheral nerves, dorsal roots, and posterior columns deprives the cerebellum of sensory input that is necessary to coordinate movement.

Question 39

Autosomal dominant spinocerebellar ataxias (ADSCAs).

Answer 39

There is no other group of neurodegenerative diseases with the clinical and pathological diversity of the ADSCAs.

This diversity is even more impressive considering that all these diseases have a common underlying molecular defect, namely CAG triplet expansion. If the expansion lies in a coding sequence, it is translated into a polyglutamine (polyQ) stretch of the affected protein.

Similar to Huntington’s disease (which is also caused by CAG repeats), the ADSCAs show the phenomenon of anticipation, i.e. lengthening of the CAG repeat with earlier onset and more severe disease in successive generations.

The expansion occurs more often with paternal transmission.

• The core neuropathology is cerebellar degeneration

Question 40

Demyelinating Diseases

Answer 40

(Primarily destruction of myelin….not neurons)

Multiple Sclerosis
Neuromyelitis Optica (NMO)
Progressive multifocal leukoencephalopathy
Guillain-Barre Syndrome (Acute Inflammatory Demyelinating Polyneuropathy)

Question 41

Neuromyelitis Optica (NMO):

Answer 41

Bilateral (painful) optic neuritis and spinal cord demyelination.

women&raquo_space; men
Poor recovery

• Auto Abs against aquaporin-4, a water channel of astrocytes (can monitor disease response with serum titers)

Tx: plasmaphoresis +/- anti CD20 Ab therapy

Question 42

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML

Answer 42

deadly demyelinative disease of the CNS due to lytic infection of oligodendrocytes by polyoma virus JC(JCV).

acquire this virus at a young age.

After primary infection–> latent in the kidneys and lymphoid tissues for life.

reactivated when cellular immunity is suppressed: AIDS, cancer and inflammatory disorders, and organ transplant recipients.

Question 43

Guillain-Barre Syndrome

Answer 43

• demyelination of spinal nerve roots and peripheral nerves

Question 44

Multiple Sclerosis

Answer 44

Autoimmune demyelinating disease with relapsing and remitting episodes of neurologic loss separate in time in areas of white matter separate in space.

Pathophysiology:
- TH1 and TH17 lymphocytes react to myelin antigens (Type IV hypersensitivity)
Humoral immunity is involved with production of IgG oligoclonal bands in the CSF

Loss of myelin sheath–> loss of salutatory conduction. There is an initial temporary conduction block followed by reorganization with slower continuous propagation of the signal

Histology of an active plaque shows lymphocytes with lipid-laden macrophages. Inactive plaque shows loss of oligodendrocytes, astrocyte proliferation and gliosis causing grossly firm areas (sclerosis)

Strong geographic link to living in Northern latitudes before age 5 years

Mild genetic effect, polymorphic

Question 45

Presentation OF MS

Answer 45

Female, young adult

sensory loss (paresthesias)
spinal cord: motor, including cramping; autonomic, esp. incontinece
Optic neuritis: presenting symptom in 20% of patients. Loss of vision or pain on movement.
- internuclear opthalmoplegia: interruption of fibers of medial long fasciculus –> eye lacks adduction–> diplopia)
Constitutional symptoms: fatigue, depression

signs: upper motor neuron signs, neurologic defects corresponding to conduction loss

Question 46

DX and history of MS

Answer 46

clinical picture: more than one attack; more than one lesion

Imagine: MRI. T2-weighted studies show active plaques (edema); T1-weighted lesions show atrophy and “black holes” of neuronal loss
CSF: not used routinely, but IgG oligoclonal bands commonly present.

Natural history: 30% have significan disability by 20 years
survival is linked to disability
treatment is corticosteroids for acute attacks, immune modulation for chronic control (esp. interferon-beta)

Question 47

NMO (= Devic’s) vs MS

Answer 47

Distribution: devics- optic nerves and spinal cord
MS: any white matter track

severe in devics, milder in MS

Head MRI normal/ non-specific in devics; multiple periventricular white matter lesions in MS

• Spinal cord MRI–longitudinally extensive central necrotic lesions in devics; in MS small peripheral lesions or nothing

CSF- pleocytosis during attacks (devics), rarely over 25 white cells in MS

oligoclonal bands- usually absent in devics, usually present in MS

Question 48

CSF DD findings of protein

Answer 48

increased in bacterial, viral, TB and Guillain Barre

but NORMAL (monoclonal bands) in MS

Question 49

CENTRAL PONTINE MYELINOLYSIS (CPM)

Answer 49

now regarded as an osmotic demyelination syndrome.
It occurs in hyponatremic patients when hyponatremia is corrected rapidly and in patients with severe hyperosmolality that was not preceded by hyponatremia. The key triggering factor is thought to be a dysosmolar state in the course of which electrolytes and organic osmolytes move out of brain cells into the extracellular space.

• symmetric