Neurodegenerative demyelinating diseases (Gianani) Flashcards
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:
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
Cortical -
- Alzheimer’s disease
- Frontotemporal dementias ,Pick’s disease
- Diffuse Lewy body disease
- Corticobasal degeneration
Midbrain
- ** 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)
Caudate nucleus
Huntington’s disease
Spinocerebellar degenerations
(CAG repeat syndromes)
- Spinocerebellar ataxias
- Friedreich’s ataxia
Motor system
(Upper cerebral cortex and lower motor neurons in brain stem and spinal cord )- Amyotrophic lateral sclerosis
- Spinomuscular atrophy
Mechanisms of cellular damage
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
Liver: α1-Antitrypsin Deficiency
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..
Protein Misfolding and Aggregation (mainly know the list of proteins)
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
Prions or prion type of behavior of proteins in
neurodegenerative disorders
“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.”
Alzheimer Disease
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
alzheimer’s Signs and Symptoms
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
Genetics of Familial AD
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)
main things to know about alzheimer’s
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.
CEREBRAL AMYLOID ANGIOPATHY
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.
PICK’S DISEASE
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)
AD: plaques composed of
dystrophic neurites
beta amyloid
tau
AD: tangles composed of
tau
both intracellular and extracellular
Progressive supranuclear palsy
(not important)
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.
Parkinson Disease (PD)
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.
Etiology of Parkinson Disease
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.
basal ganglia info
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.
The presumptive diagnosis of PD
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.
Deep brain stimulation (DBS
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.
pathogenesis of parkinsonism
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.
result of lewy bodies
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).
DIFFUSE LEWY BODY DISEASE
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.
Multiple System Atrophy (not important)
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.
Huntington Disease
- 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?
The gene for HD
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.
If there are more than 36 CAG repeats =
“Repeat expansion” = HD
4p16.3
–> abnormally long string of glutamines
Trinucleotide repeat distorders
There are three key mechanisms by which unstable repeats cause diseases:
(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.
Huntington’s- destruction of
the caudate
What residual tissue is left behind after the caudate is destroyed is replaced by gliosis…glial cells stain GFAP +
Huntington’s Disease etiology, manifestations, treatment
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
cortex involvement in basal ganglia movement disorders
parkinson- hypoactive cortex
Huntington- hyperactive cortex
hemiballismus- hyperactive cortex
Amyotrophic Lateral Sclerosis (ALS)
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.
ATAXIA AND CEREBELLAR DEGENERATION
not discussed by Gianani
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.
Friedrich’s ataxia
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.
Autosomal dominant spinocerebellar ataxias (ADSCAs).
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
Demyelinating Diseases
(Primarily destruction of myelin….not neurons)
Multiple Sclerosis
Neuromyelitis Optica (NMO)
Progressive multifocal leukoencephalopathy
Guillain-Barre Syndrome (Acute Inflammatory Demyelinating Polyneuropathy)
Neuromyelitis Optica (NMO):
Bilateral (painful) optic neuritis and spinal cord demyelination.
women»_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
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML
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.
Guillain-Barre Syndrome
- demyelination of spinal nerve roots and peripheral nerves
Multiple Sclerosis
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
Presentation OF MS
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
DX and history of MS
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)
NMO (= Devic’s) vs MS
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
CSF DD findings of protein
increased in bacterial, viral, TB and Guillain Barre
but NORMAL (monoclonal bands) in MS
CENTRAL PONTINE MYELINOLYSIS (CPM)
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