Creutzfeldt Jakob Disease

Slide 1 · Creutzfeldt–Jakob Disease

Prion pathogenesis · clinicopathologic progression · diagnosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain how misfolded PrP propagates and causes prion disease.

Distinguish sporadic, genetic, and iatrogenic CJD.

Recognize the clinical course and characteristic neuropathology.

Apply current clinical criteria while identifying diagnostic limitations.

Integrate infection-control and patient-care implications.

Slide 3 · Disease concept: An accelerated proteinopathy

CJD is a rapidly progressive, fatal neurodegenerative prion disease.

It is the most common human prion disease.

Misfolded prion protein is central to pathogenesis.

Spongiform gray-matter change characterizes neuropathology.

Slide 4 · CJD within the neurodegenerative diseases

Shared framework

Selective neuronal injury

Abnormal protein aggregation

Clinical pattern reflects the affected neural systems

Prion disease distinction

Misfolded PrP can template further PrP conversion

Intercellular propagation is a defining pathogenic feature

CJD typically progresses over months

Slide 5 · Human prion disease spectrum

Human disorder

Context in this lecture

Classic CJD

Principal focus: sporadic, familial, iatrogenic

Variant CJD

Distinct exposure-linked disease; short comparison

Gerstmann–Sträussler–Scheinker syndrome

Inherited prion disease; differential context

Fatal familial insomnia

Inherited prion disease; differential context

Kuru

Acquired prion disease; transmission example

Slide 6 · Classic versus variant CJD: Maintain the distinction

Classic CJD

Typically occurs in older adults

Usually sporadic

Rapid dementia prominent early

Variant CJD

Associated with BSE exposure

Often affects younger individuals

Psychiatric / sensory symptoms may precede dementia

Slide 7 · Rarity of sporadic CJD

Textbook estimate: Approximately 1 case per million people annually.

Sporadic CJD as more than 90% of CJD cases.

Current CDC estimates: Approximately 1–2 CJD cases per million annually.

These figures reflect different sources; Do not treat them as identical estimates.

Slide 8 · Disease-form proportions differ across references

Robbins (11th edition)

Sporadic form: More than 90% of CJD cases

Familial forms less common

Iatrogenic CJD documented

CDC clinical overview (2026)

Sporadic: About 85%

Familial: About 5–15%

Iatrogenic: Less than 1%

Slide 9 · Age distribution of classic CJD

Peak incidence in the seventh decade.

CDC notes that CJD typically affects adults aged 55 years and older.

Age modifies pretest suspicion; It does not establish the diagnosis.

Younger onset requires attention to genetic and variant phenotypes.

Slide 10 · Three pathways to the same misfolded protein

Sporadic

Rare spontaneous PrP conformational change

Familial

PRNP mutation favors abnormal conformational change

Iatrogenic

Introduction of exogenous abnormal PrP

Distinct initiating circumstances converge on amplification of abnormal PrP in neural tissue.

Slide 11 · What PRNP contributes to disease

PRNP encodes the host prion protein, PrP.

Inherited PRNP mutations can increase the tendency toward pathogenic misfolding.

Familial CJD is one of several inherited human prion disorders.

Mutation-associated disease is conceptually distinct from acquired exposure.

Slide 12 · Documented iatrogenic exposures

Exposure route

Clinical significance

Corneal transplantation

Transmitted CJD has been documented

Dural transplantation

Transmitted CJD has been documented

Intracerebral depth electrodes

Historical transmission via contaminated equipment

Cadaveric growth-hormone preparations

Historically transmitted disease

Slide 13 · Transmission is not ordinary interpersonal contagion

Potentially hazardous exposure

Contaminated neural tissue / instruments

Certain transplanted biological products

Specialized reprocessing for neurosurgery

Routine contact

CJD does not spread through normal personal contact

No airborne-droplet transmission

Standard interpersonal interaction is not the iatrogenic route

Slide 14 · Normal PrP versus disease-associated PrP

PrPᶜ

Predominantly α-helical conformation

Protease-sensitive

Conformational transition

Misfolding of host protein

No change in PRNP sequence required

PrPˢᶜ

Increased β-sheet structure

Relatively protease-resistant

The central event is a change in protein conformation, not replication of nucleic acid.

Slide 15 · A protein without a conventional genome

PrPˢᶜ can induce PrPᶜ to assume its abnormal conformation.

Host PrP provides the substrate for amplification.

The pathogenic template is the misfolded protein itself.

Propagation can proceed after the initiating event.

Slide 16 · Proteinase K resistance: Diagnostic meaning

The abnormal conformer is more resistant to proteolysis than PrPᶜ.

Protease treatment enriches detection of disease-associated PrP.

Tissue immunostaining after partial proteolysis demonstrates PrPˢᶜ.

Protease resistance is a biochemical property, not a clinical symptom.

Slide 17 · Sporadic initiation: The low-probability event

Normal protein pool

PrPᶜ is present in host tissue

Rare structural change

A small amount converts to PrPˢᶜ

Templated amplification

PrPˢᶜ converts additional PrPᶜ

CNS accumulation

Abnormal protein aggregates

A rare initiation step can be magnified through self-propagating conversion.

Slide 18 · Inherited initiation: Altered conversion propensity

Germline PRNP variant

Genetically altered PrP

Higher misfolding tendency

Conformational transition favored

PrPˢᶜ propagation

Further native PrP converted

Neural injury

Accumulation-associated damage

Genetic risk changes the propensity for conversion; The propagation principle is shared.

Slide 19 · Iatrogenic initiation: Introduction of a seed

Contaminated material

Prion-containing tissue or preparation

Exposure to recipient

Abnormal PrP reaches susceptible tissue

Conformational seeding

Recipient PrPᶜ becomes PrPˢᶜ

Amplification

Self-propagating accumulation

The infectious property follows from seeded protein misfolding.

Slide 20 · Self-propagation: A molecular cascade

PrPˢᶜ

Existing abnormal conformer

PrPᶜ contact

Normal substrate interacts

Conformational conversion

New PrPˢᶜ is generated

Growth

Increasing pool of abnormal conformers

Templating links a molecular event to exponential-looking propagation; No growth curve is implied.

Slide 21 · Propagation versus accumulation

Propagation

Cell-associated conversion of PrPᶜ into PrPˢᶜ

Can account for transmission between tissues / hosts

Requires native protein substrate

Accumulation

PrPˢᶜ persists and aggregates in nervous tissue

Correlates with neuropathologic injury

Specific downstream toxicity mechanisms remain incompletely understood

Slide 22 · What is established—and what remains uncertain

PrPˢᶜ accumulation is strongly linked to neural injury.

Spongiform change and neuronal loss as outcomes.

The precise route from PrP aggregation to cytoplasmic vacuoles is unresolved.

Avoid assigning a single unverified molecular toxicity pathway.

Slide 23 · Histopathologic signature

Spongiform transformation of gray matter is the hallmark.

Microscopic vacuoles are variably sized and multifocally distributed.

The cerebral cortex and deep gray nuclei are important sites.

In advanced disease: Neuronal loss, gliosis, and status spongiosus.

Slide 24 · Anatomic distribution of spongiform change

Cerebral cortex

Caudate

Putamen

Conceptual region map; Not anatomical proportions

Cerebral cortex is prominently involved.

The caudate and putamen are named deep-gray targets.

The lesion is multifocal and unevenly distributed.

A conceptual region map does not depict specimen anatomy.

Slide 25 · Spongiform change in the neuropil: Schematic

Schematic illustration — not a clinical/histologic specimen

01

Unevenly distributed clear vacuoles

02

Microscopic neuropil involvement

03

Neuron perikarya may also contain vacuoles

Slide 26 · The neuropil is a major compartment of injury

Small clear spaces interrupt the background of neuronal processes.

Vacuoles vary in diameter rather than forming identical, regular pores.

The distribution can be patchy within involved gray matter.

Histologic vacuolation requires clinicopathologic interpretation.

Slide 27 · Vacuoles can extend into neuronal perikarya

Schematic illustration — not a clinical/histologic specimen

01

Unevenly distributed clear vacuoles

02

Microscopic neuropil involvement

03

Neuron perikarya may also contain vacuoles

Slide 28 · Histologic progression within gray matter

Early / less advanced

Scattered variably sized vacuoles

Neuropil remains largely identifiable

Gross atrophy may be minimal

Advanced / destructive

Marked neuronal loss

Reactive gliosis

Larger confluent vacuolated spaces

Slide 29 · Advanced spongiform injury

Schematic illustration — not a clinical/histologic specimen

01

Confluent vacuolated areas

02

Few remaining neurons

03

Severe tissue destruction

Slide 30 · Neuronal loss links morphology to decline

Loss of functional neurons compromises neural circuits.

Neuronal loss can become severe in advanced spongiform lesions.

Distribution across cortical and subcortical gray matter helps explain global neurologic dysfunction.

This is a clinicopathologic interpretation, not a quantitative causal model.

Slide 31 · Reactive gliosis accompanies advanced injury

Schematic illustration — not a clinical/histologic specimen

01

Vacuolated neuropil

02

Neuronal injury / loss

03

Reactive gliosis in advanced lesions

Slide 32 · A notable negative finding: Little inflammation

Inflammation is notably absent despite marked tissue damage.

CJD is not characterized by a conventional inflammatory encephalitis pattern.

Absence of substantial inflammation helps characterize the lesion.

A noninflammatory biopsy alone is not sufficient to establish CJD.

Slide 33 · Status spongiosus: Late tissue destruction

Multifocal vacuoles

Individual microscopic spaces

Expansion

Vacuolated areas become larger

Confluence

Cyst-like spaces (status spongiosus)

Loss

Marked neuronal depletion

“Status spongiosus” describes advanced morphologic change, not a disease subtype.

Slide 34 · Electron-microscopic correlate

Membrane-bound vacuoles on electron microscopy.

These vacuoles occur within the cytoplasm of neuronal processes.

The ultrastructural finding complements—but does not replace—routine histology.

It is distinct from extracellular amyloid plaque material.

Slide 35 · Why gross cerebral atrophy may be limited

Typical rapid course

Functional deterioration is fast.

There is often little grossly visible cerebral atrophy.

Microscopic damage can be marked despite a subtle gross examination.

Long-surviving cases

A minority survive for years.

Extensive gray-matter atrophy may develop.

Long duration allows cumulative tissue loss to become grossly apparent.

Slide 36 · Demonstrating the disease-associated protein

Brain tissue

Histologic specimen

Proteinase K

Partial digestion of PrPᶜ

PrP immunostain

Demonstrates resistant deposits

Interpretation

Supports prion disease in appropriate context

The target is disease-associated PrPˢᶜ; Staining is not a generic marker of dementia.

Slide 37 · Kuru plaques: Deposited PrP amyloid

Kuru plaques contain extracellular aggregates of abnormal PrP.

They can stain with Congo red and periodic acid–Schiff (PAS).

Their usual occurrence in the cerebellum.

Abundant cortical plaques are particularly associated with variant CJD.

Slide 38 · Spongiosis versus PrP plaques

Spongiform change

Clear microscopic vacuoles

Involves neuropil and sometimes neuronal cell bodies

The central architectural lesion

Kuru plaques

Extracellular deposits of aggregated abnormal PrP

Amyloid-type histochemical staining

Distribution differs among prion disease forms

Slide 39 · Integrating the key neuropathology findings

Observation

Interpretation / limitation

Vacuolated gray-matter neuropil

Classic spongiform pattern

Neuronal depletion

Advanced neurodegenerative injury

Reactive gliosis

Reaction to ongoing tissue damage

Little inflammation

Characteristic negative clue

Protease-resistant PrP

Disease-associated protein evidence

Slide 40 · Clinical evolution of classic CJD

Subtle onset

Memory and behavior changes

Progression

Rapid deterioration in cognition

Neurologic features

Myoclonus ± cerebellar dysfunction

Advanced disease

Severe disability and death

Sequence is schematic: Not every patient has every manifestation or the same interval.

Slide 41 · Initial cognitive and behavioral disturbance

Early memory changes may be subtle.

Behavioral disturbance can precede overt dementia.

The time course is often more discriminating than an isolated symptom.

Serial clinical history is essential to recognize rapid progression.

Slide 42 · Rapidly progressive dementia is central

A steep cognitive decline over months is the characteristic presentation.

CJD can move rapidly from mild cognitive changes to profound impairment.

Early course may overlap with other causes of cognitive decline.

The disease’s tempo is a major clinicopathologic clue.

Slide 43 · Startle myoclonus

Sudden sensory stimulation may trigger prominent involuntary muscle jerks.

Startle myoclonus is a characteristic feature.

A single sign does not independently establish CJD.

Movement phenomena occur alongside progressive cognitive dysfunction.

Slide 44 · Cerebellar involvement: Clinical expression

Cerebellar dysfunction can manifest as ataxia.

Ataxia in a minority of affected patients.

The absence of ataxia does not exclude classic CJD.

Visual or cerebellar signs are also used in current clinical criteria.

Slide 45 · Clinical features and plausible anatomic context

Clinical observation

Clinicopathologic context

Progressive dementia

Widespread cerebral cortical dysfunction

Ataxia

Cerebellar system dysfunction

Startle myoclonus

Abnormal motor-system excitability

Behavioral change

Disruption of distributed cognitive networks

Anatomic correlations are explanatory; They are not a one-to-one lesion map.

Slide 46 · Prognosis is severe

Mean survival of about 7 months after symptom onset.

The textbook characterizes CJD as uniformly fatal.

CDC reports a median of approximately 4–5 months in its clinical overview.

Mean and median are different summary statistics; Do not equate them.

Slide 47 · Diagnostic framing: Suspected to definite

Modern clinical assessment uses graded diagnostic certainty.

Possible CJD: Compatible syndrome without qualifying supportive evidence.

Probable CJD: Qualifying clinical features plus RT-QuIC or other supportive testing.

Definite CJD: Neuropathologic / tissue-based confirmation.

The CDC criteria here are a contemporary supplement to Robbins, not a quotation from the textbook.

Slide 48 · MRI as a supportive diagnostic test

Current CDC probable-CJD criteria include high signal in the caudate or putamen.

Alternatively, signal in at least two specified cortical regions may qualify.

Accepted sequences include DWI or FLAIR.

Imaging findings must be integrated with syndrome and alternative diagnoses.

Slide 49 · EEG: A characteristic supportive pattern

Typical EEG can show periodic sharp-wave complexes.

A qualifying EEG can support probable sporadic CJD under the CDC pathway.

EEG is not the sole criterion for clinical diagnosis.

A nondiagnostic EEG does not by itself exclude CJD.

Slide 50 · CSF neuronal injury marker versus prion assay

CSF 14-3-3

Marker used within a specified clinical diagnostic pathway

CDC criterion applies when illness duration is <2 years

Not equivalent to direct prion-seeding detection

CSF RT-QuIC

Amplifies PrP misfolding initiated by disease-associated seed

Positive test plus neuropsychiatric disorder supports probable CJD

Assay performance differs by prion disease subtype

Slide 51 · RT-QuIC: Assay logic

Patient sample

CSF or another validated tissue

Seed addition

Potential disease-associated PrP

Amplification

Misfolding of substrate protein

Readout

Evidence of templated aggregation

A positive assay is powerful support but a negative assay cannot exclude every phenotype.

Slide 52 · CDC probable sCJD: RT-QuIC pathway

A neuropsychiatric disorder plus a positive RT-QuIC assay.

RT-QuIC positivity in CSF or other tissues is the laboratory requirement.

This is one independent route to a probable sporadic CJD classification.

Laboratory evidence is interpreted alongside the clinical syndrome.

Slide 53 · CDC probable sCJD: Multimodal pathway

Rapidly progressive dementia plus at least 2 of 4 clinical features.

Clinical features: Myoclonus; Visual/cerebellar signs; Pyramidal/extrapyramidal signs; Akinetic mutism.

Additionally, ≥1 qualifying test: Periodic sharp-wave EEG, appropriate CSF 14-3-3, or defined MRI abnormality.

Routine investigation must not suggest an alternative diagnosis.

Slide 54 · CDC possible sporadic CJD

Progressive dementia with at least 2 of the 4 specified features.

Features: Myoclonus, visual/cerebellar signs, pyramidal/extrapyramidal signs, akinetic mutism.

No positive qualifying test that would establish probable CJD.

Disease duration <2 years, and no alternative diagnosis on routine evaluation.

Slide 55 · A disciplined suspected-CJD workup

History and examination

Rapid progression; Neurologic signs

MRI / EEG / CSF

Check defined supportive tests

RT-QuIC where available

Evaluate prion-seeding evidence

Confirmatory pathway

Specialist tissue assessment when indicated

Throughout the evaluation, consider potentially treatable alternative causes of rapid cognitive decline.

Slide 56 · Definite CJD: Tissue-based evidence

CDC includes neuropathologic examination for confirmation.

Disease-associated protease-resistant PrP can be demonstrated immunochemically or by Western blot.

Scrapie-associated fibrils are another recognized confirmatory feature.

Brain biopsy is not required for every clinically probable case.

Slide 57 · Recognizing a diagnostic limitation

No single clinical symptom proves CJD.

A compatible syndrome and appropriate laboratory evidence establish graded probability.

RT-QuIC sensitivity varies among prion disease phenotypes.

Routine evaluation must actively consider alternative explanations.

Slide 58 · Why each diagnostic modality contributes

Modality

Distinct contribution

Clinical history

Tempo and neurologic phenotype

MRI (DWI / FLAIR)

Pattern of gray-matter signal abnormality

EEG

Characteristic electrophysiologic pattern

CSF 14-3-3

Supportive injury-related biomarker in defined context

RT-QuIC

Disease-associated prion-seeding assay

Neuropathology

Confirmatory tissue assessment

Slide 59 · Classic CJD and variant CJD: High-yield contrasts

Feature

Classic CJD

Variant CJD

Age distribution

Predominantly older adults

Typically younger adults

Early symptom pattern

Rapid cognitive decline

Psychiatric / sensory changes

Pathologic emphasis

Spongiosis in gray matter

Prominent cortical florid / kuru-type plaques

Exposure association

Usually sporadic

Linked to BSE exposure

Clinical time course

Generally faster

Relatively slower

Slide 60 · BSE-linked disease must not be misclassified

Variant CJD is distinct from classic sporadic CJD.

Young onset and behavioral symptoms early in variant CJD.

The BSE exposure link belongs to variant CJD.

Do not imply that sporadic classic CJD is contracted by eating beef.

Slide 61 · Instrument and tissue precautions

Prion infectivity is unusually resistant to routine decontamination.

Exposure concern is greatest for brain, spinal cord, and ocular tissues.

CDC provides dedicated protocols for contaminated surgical instruments.

Use institutional infection-control procedures; Do not improvise sterilization protocols.

Slide 62 · Risk communication in clinical settings

Avoid false reassurance

Histology and brain-instrument exposure require special handling

Potential iatrogenic transmission is a documented risk

Specialist laboratory coordination matters

Avoid unnecessary isolation stigma

CJD is not spread by ordinary contact

Standard care and supportive interaction remain appropriate

Explain the difference between routine contact and high-risk tissue exposure

Slide 63 · Management and patient-care implications

There is no therapy proven to stop or slow classic CJD progression.

Care centers on symptom relief, safety, and functional support.

The rapid clinical course makes early planning and caregiver communication important.

A diagnosis should be based on an appropriate specialist evaluation.

Slide 64 · Case 1: Rapid decline with myoclonus

A 68-year-old develops memory changes, progressive dementia, and stimulus-induced jerks over several months.

Which disease mechanism best accounts for the clinical tempo?

Which major microscopic pattern would you expect?

What additional evidence could support a probable diagnosis?

Slide 65 · Case 1: Integrated interpretation

Mechanism

Self-propagating PrP misfolding

Expected morphology

Spongiform gray-matter change

Supportive workup

MRI, EEG, CSF; RT-QuIC

Conclusion

Clinical suspicion requires integrated evaluation

Case is a hypothetical teaching scenario; No individual patient data are represented.

Slide 66 · Case 2: Exposed tissue versus family history

Two patients have rapid neurologic deterioration: One has a PRNP-linked family history, the other a remote cadaveric tissue exposure.

What distinguishes inherited from iatrogenic initiation?

What step in prion propagation is shared by both?

Which history prompts specialized risk communication?

Slide 67 · Case 2: Contrasting initiators

Inherited

PRNP alters protein misfolding tendency

Iatrogenic

Exogenous prion seed introduced

Convergence

PrPˢᶜ propagates through PrPᶜ conversion

Shared result

Spongiform neurodegeneration

Different routes of initiation can produce the same propagation mechanism.

Slide 68 · Microscopy checkpoint: Interpret the pattern

Gray matter shows multifocal small vacuoles, neuronal loss, gliosis, and no appreciable inflammation.

Name the defining architectural pattern.

Which protein assay can demonstrate disease-associated deposition?

Why does minimal gross atrophy not exclude this diagnosis?

Slide 69 · Five teaching conclusions

CJD is the most common human prion disease and usually progresses rapidly.

Misfolded PrP propagates by templated conversion of host PrP.

Spongiform gray-matter change is the central morphologic pattern.

Probable diagnosis uses clinical features plus defined test evidence.

Tissue confirmation and specialist infection-control practices remain important.

Slide 70 · Selected sources and figure provenance

Robbins, Cotran & Kumar. Pathologic Basis of Disease, 11th ed. (2026). Ch. 28, pp. 1159–1161.

CDC. Clinical Overview of Creutzfeldt-Jakob Disease. Updated January 21, 2026.

CDC. Infection Control for CJD. Updated January 21, 2026.

CDC. Clinical Overview of Variant CJD. November 12, 2024.

Rhoads DD et al. Diagnosis of prion diseases by RT-QuIC results in improved surveillance. Neurology. 2020.

All tissue illustrations in this presentation are original, labeled schematics; no diagnostic photographs were reproduced.