Prion Disease / Degenerative Diseases

Dr. Reetu Baral MDAssociate Professor Department of Pathology

Transmissable Spongiform Encephalopathies (Prion Diseases)

Group of diseases: – Creutzfeldt-Jacob disease (CJD)– Gerstmann-Straussler-Scheinker syndrome GSS– Fatal Familial Insomnia– Kuru in humans– Scrapie in sheep and goats– Bovine Spongiform Encephalopathy (BSE)

• Characterized by “Spongiform change” caused by intracellular vacuoles in neurons and glia.

Prion diseases

• These maybe: – Sporadic,– Familial, – Iatrogenic, and

• They can be sporadic, transmitted, or inherited.

• Clinically most of the patients develop dementia.

Prion diseases

• The agent - abnormal form of a cellular protein. • Termed: prion protein (PrP) - undergoes a

conformational change from its normal shape (PrPc) to an abnormal conformation called PrPsc

(sc for scrapie).• PrP normally is rich in α-helices,• PrPsc has a high content of β-sheets, a

characteristic that makes it resistant to proteolysis (hence an alternative term for the pathogenic form, PrPres— protease resistant).

Prion diseases• When PrPsc physically interacts with PrP

molecules - induces them to also adopt the PrPsc conformation- “infectious nature”

• Over time, this self amplifying process leads to the accumulation of a high burden of pathogenic PrPsc molecules in the brain.

• PrPc also may change its conformation spontaneously (but a extremely low rate), accounting for sporadic cases of prion disease (sCJD).

Prion diseases• Certain mutations in the gene encoding PrPc

(PRNP) accelerate the rate of spontaneous conformational change.

• These variants are associated with early onset familial forms of prion disease (fCJD).

• Accumulation of PrPsc in neural tissue seems to be the cause of cell injury,

• The mechanisms underlying the cytopathic changes and eventual neuronal death are still unknown.

Pathogenesis•α-Helical PrPc may shift to the β-sheet PrPsc conformation –higher rate in familial disease associated with germ line PrP mutations. •PrPsc : exogenous sources- contaminated food, medical instrumentation, or medicines. •PrPsc converts additional molecules of PrPc into PrPsc through physical Interaction- formation of pathogenic PrPsc aggregates.

Creutzfeldt-Jakob Disease• Rapidly progressive dementing illness- first onset of

subtle changes in memory and behavior to death- 7 months.

• It is sporadic in approximately 85% of cases and has a worldwide annual incidence of about 1 per million.

• Commonly seen in 70 years or older • Familial forms caused by mutations in PRNP may

present in younger people. • Well-established cases of iatrogenic transmission -

contaminated deep implantation electrodes and contaminated human growth hormone preparations.

MORPHOLOGY: CJD• Progression of disease to death – very rapid – no macroscopic evidence of brain atrophy.

• Spongiform transformation of the cerebral cortex and deep gray matter structures (caudate, putamen);

• Uneven formation of small, vacuoles of varying sizes within the neuropil and sometimes in the perikaryon of neurons.

• No inflammatory infiltrate is present.

Variant Creutzfeldt-Jakob Disease• 1995 - CJD-like illness appeared in the United

Kingdom.• Affects young adults• Behavioral disorders – prominent - in early

disease stages.• Neurologic syndrome -progressed more slowly -

than in other forms of CJD.• Variant Creutzfeldt-Jakob disease (vCJD) – due

to exposure to the prion disease of cattle, called bovine spongiform encephalopathy.

• There has now also been documentation of transmission by blood transfusion.

Variant CJD (vCJD)

• Is characterized by amyloid plaques that sit in the regions of greatest spongiform change.

NEURODEGENERATIVE DISEASES

• Degenerative diseases of the CNS are disorders characterized by the cellular degeneration of subsets of neurons that typically are related by function, rather than by physical location in the brain.

• Associated with the accumulation of abnormal proteins.

NEURODEGENERATIVE DISEASES

Those that affect the:• Cerebral cortical neurons result in loss of

memory, language, insight, and planning, all components of dementia;

• Neurons of the basal ganglia result in movement disorders;

• Cerebellum result in ataxia; • Motor neurons result in weakness.

NEURODEGENERATIVE DISEASES

• Dementia is defined as the development of memory impairment and other cognitive deficits severe enough to decrease the affected person’s capacity to function at the previous level despite a normal level of consciousness.

• It arises during the course of many neurodegenerative diseases and numerous other diseases that injure the cerebral cortex.

Alzheimer Disease• Most common cause of dementia in the elderly

population.• Manifestations: insidious onset of impaired

higher intellectual function and altered mood and behavior.

• Progresses to disorientation, memory loss, and aphasia, findings indicative of severe cortical dysfunction.

• After 5 to 10 years, the patient becomes profoundly disabled, mute, and immobile.

• Death: Pneumonia or other infections.

Alzheimer Disease

Incidence: – 3% in persons 65 to 74 years old, – 19% in those 75 to 84 years old,– 47% in those older than 84 years.

• Most cases of AD are sporadic, but at least 5% to 10% are familial.

• Sporadic cases rarely present before 50 years of age.

PATHOGENESIS: Alzheimer Disease

• A peptide called beta amyloid, or Aβ, accumulates in the brain over time, initiating a chain of events that result in AD.

• Aβ is created when the transmembrane protein amyloid precursor protein (APP) is sequentially cleaved by the enzymes β-amyloid converting enzyme (BACE) and γ-secretase.

Morphology : AD• Macroscopic: The brain shows cortical

atrophy, resulting in a widening of the cerebral sulci mostly in the frontal, temporal, and parietal lobes.

• With significant atrophy, there is compensatory ventricular enlargement (hydrocephalus ex vacuo).

• Microscopic: AD is diagnosed by the presence of plaques (an extracellular lesion); and neurofibrillary tangles (an intracellular lesion)

Morphology: AD• Neuritic plaques: – are focal, spherical

collections of dilated, tortuous, silver-staining neuritic processes often around a central amyloid core.

Morphology: AD• Neurofibrillary tangles are bundles filaments in the cytoplasm of the neurons that displace or encircle the nucleus.

• Neurofibrillary tangles are insoluble and can persist as ghost or tombstone tangles even after the death of the parent neuron.

Parkinson Disease• Parkinsonism is a clinical syndrome

characterized by: – Pill rolling tremor, Rigidity, – Bradykinesia, Instability,– Diminshed facial expression, stooped posture,– Festinating gait.

• These types of motor disturbances may be seen in a range of diseases that damage dopaminergic neurons, which project from the substantia nigra to the striatum.

Parkinson Disease

• Parkinson disease(PD)- associated with characteristic neuronal inclusions containing α-synuclein.

• Parkinsonism may be present: – Multiple system atrophy (MSA), in which α-

synuclein aggregates are found in oligodendrocytes;

– Progressive supranuclear palsy (PSP) and – Corticobasal degeneration (CBD)- both associated

with tau-containing inclusions in neurons and glial cells;

– Postencephalitic parkinsonism, which was associated with the 1918 influenza pandemic.

PD: PATHOGENESIS

• Mostly sporadic.• Maybe autosomal dominant and recessive. • Point mutations and duplications of the gene

encoding α-synuclein, a protein involved in synaptic transmission, cause autosomal dominant PD.

• The diagnostic feature of the disease—the Lewy body—is an inclusion containing α-synuclein.

PD: MORPHOLOGY• Gross finding: Pallor of

the substantia nigra and locus ceruleus.

PD: Morphology• M/E include loss of the pigmented, catecholaminergic neurons -associated with gliosis.

• Lewy bodies: Are composed of fine filaments, densely packed in the core but loose at the rim.

PD: Clinical Features

• Movement disorder in the absence of a toxic exposure or underlying etiology.

• The disease usually progresses over 10 to 15 years - severe motor slowing to the point of near immobility.

• Death -intercurrent infection or trauma-frequent fall.• Movement symptoms initially respond to L-

dihydroxyphenylalanine (L-DOPA), but this treatment does not slow disease progression.

• Over time, L-DOPA becomes less effective and begins to cause potentially problematic fluctuations in motor function.

PD: Clinical Features

• In advanced cases: Autonomic dysfunction and behavioral disorders.

• Involvement of Cerebral cortex: Dementia, Hallucinations.

• When dementia arises within 1 year of the onset of motor symptoms, it is referred to Lewy body dementia (LBD).

The end