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AMYLOID: PATHOLOGY

Stain methods Muscle   Fibers   ANO5   Dysferlin   FKRP   IM-VAMP Nerve Vessels   1° Amyloid   LGMD 2B TTR Mutations   Val30Met   Thr60Ala M-proteins   IgAκ   IgAλ   IgGλ Ultrastructure   Vessels   Fibrils   Spherulites

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MUSCLE

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Amyloid myopathy Amyloid (Red): Locations Extracellular Tissues Muscle fibers: Around surface Perimysium Vessel walls Amyloid properties: Apple green birefringence of amyloid Amyloid Components Hereditary Apolipoprotein A1, Apolipoprotein A4, Apolipoprotein E, Serum amyloid P component No Anoctamin-5 or Dysferlin Acquired: Amyloidogenic proteins (AL & SSA) Amyloid in IM-VAMP (IBM) Intracellular aggregates (β-amyloid protein), or Near Vacuoles

Congo red

Congo red (Polarized light)

Congo red (Fluorescence)

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Amyloid Muscle Fibers

Amyloid surrounding, and on, muscle fibers

• Mild pathology (Above): Thin layer of amyloid around normal sized muscle fiber
• More severe changes (Below)
  • Thick deposit of amyloid around, and on, small muscle fibers
  • Nuclei and NADH-positive membranes are present in regions of amyloid deposits
  • Myofibrillar contractile apparatus (ATPase staining) is absent from areas of amyloid deposition but present in the center of fibers

Congo red

Congo red (Polarized light)

Congo red (Fluorescence)

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Muscle fiber pathology in amyloid myopathy

• Abnormal nuclei: In ring within muscle fibers
• Irregular deposits of amyloid: On muscle fibers outside nuclear ring

Congo red	Congo red stain
	Congo red stain
	Congo red stain (Polarized light)
Congo red, polarized light

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Congo red

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Amyloid Fibers   Muscle fiber pathology in amyloidosis Peripheral ring around muscle fibers Amyloid on Congo red Abnormal structure H&E, GT and VvG stains Contains multiple myonuclei NADH: Irregular staining ATPase stain: Reduced or Absent Sarcolemma & Basal lamina: Thickened

H&E stain

H&E stain

Gomori trichrome

VvG

Congo red

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Amyloid Fibers

VvG

Congo red

Congo red: Fluorescence

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Amyloid Fibers

ATPase pH 9.4

ATPase pH 9.4

NADH

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Dystrophin

Surface membrane (Above) & Basal lamina (Below): Thickened & reduplicated around muscle fibers

α2-Laminin

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IgAλ M-protein: Amyloid in Nerve

Congo red

Amyloid
  Congo red stained amyloid on endoneurial microvessels

Congo red

Amyloid
  Red-Green birefringent Congo red stained amyloid on endoneurial microvessels

Congo red, Polarized

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C_5b-9 stains focus of endoneurial amyloid

C5b-9

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Amyloid
  Amorphous material in wall of endoneurial vessel
  Moderate & ongoing loss of myelinated axons

Toluidine blue stain

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Amyloid
  Moderate & ongoing loss of myelinated axons

VvG stain

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Amyloid
  Axon loss: Small > Large

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Amyloid
  Non-myelinating Schwann cells: Diffusely distributed in endoneurium

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IgAκ M-protein: Amyloid in Muscle

Congo red

Amyloid deposits in perimysium and along the perimysial surface of muscle fibers

Congo red

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IgGλ M-protein: Amyloid

Congo red

Congo red

Congo red

Congo red

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NERVE: Amyloid

Patterns of axon loss

• Size
  • Moderately severe: More loss of unmyelinated & small myelinated axons than large myelinated axons
  • Severe: Loss of Large & Small axons
• Distribution: Differential loss of axons among, or within, fascicle
• Non-myelinating Schwann cells: Normal, Reduced or Increased numbers

Amyloid deposition in nerve may be

• Endoneurial
  • Capillaries
  • Multifocal
  • Diffuse
• Subperineurial
• Epineurial

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Amyloid: Distribution

• Organs: Many
• Vessels: Common
• More abundant in large nerves

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Severe Axon Loss   Marked axon loss   Small axons are even more involved than large axons   See: Control nerve Neurofilament stain

Neurofilament stain

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Moderate axon loss
Differential fascicular loss: More axon loss in some areas than others

Neurofilament stain

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Moderate axon loss

VvG stain

More loss of small axons, than larger myelinated axons

Neurofilament stain

Large axons: Moderate loss
Small axons: Severe loss

Neurofilament stain

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NCAM stain

Non-myelinating Schwann cells: Varied patterns
  Axon loss: Normal or Increased Numbers
  Amyloid deposition: Patchy loss of Schwann cells & axons

NCAM stain

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VvG From: R Bucelli

Amyloidosis
  Focal endoneurial regions have loss of cells (Arrows)

NCAM (Red); Neurofilament (Green & Yellow)

Amyloid in Endoneurium
  Patchy loss of Schwann cells & Axons (Arrows)
  Some remaining myelin is abnormal with NCAM staining (Below; Yellow)

NCAM (Green); P0 (Red)

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Congo Red From: R Bucelli

Amyloid: Multifocal Deposition
Locations
  Endoneurial connective tissue
  Around endoneurial microvessels
  Perineurium
  Epineurial connective tissue
  Epineurial vessel walls

Congo Red From: R Bucelli

Congo Red From: R Bucelli

Amyloid: Congo red birefringence
  Maltese cross pattern in some areas

Congo Red From: R Bucelli

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From: R Schmidt

Amyloid Spherulites

From: R Schmidt

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From: R Schmidt

Fibrils in Amyloid Spherulite

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Toluidine blue stain

Moderate axon loss   More loss of small, than large, myelinated axons   Subperineurial edema in some fascicles Toluidine blue stain

Toluidine blue stain

Toluidine blue stain

Amyloid Neuropathy
  Relative preservation of larger myelinated axons

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Loss of Small axons with collagen pockets

From: R Schmidt

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Amyloid Deposition

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Capillary walls: Thick
Sub-Perineurial edema

H&E stain

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Congo red stain

Capillary walls
  Contain red-stained amyloid
  Amyloid is birefringent

Congo red stain

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Endoneurial amyloid, Multifocal, often near endoneurial vessels (Arrow)

Congo red stain Congo red stain

Amyloid: Amorphous deposits surround endoneurial microvessels

Congo red stain

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Toluidine blue stain

Amyloid: Amorphous deposits around endoneurial microvessels

Toluidine blue stain

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Endoneurial amyloid, Diffuse

Congo red stain

Congo red stain

Toluidine blue stain

Amyloid: Amorphous deposits in endoneurium

Toluidine blue stain

SUBPERINEURIAL AMYLOID (Arrow) Congo red stain

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Moderate sized vessels: Amyloid

Vessels in Perimysium & Epineurium: May have amyloid deposits

Congo red stain	Congo red stain (± Polarized light)	Congo red stain (Polarized light)
Amyloid in vessel walls   Red-Stained	Birefrengence ± Polarization	Amyloid in vessel wall   Apple green     with polarized light.

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Amyloid: Artery

Congo red stain

Amyloid: Vein + Perimysium

Congo red stain

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From: R Schmidt

Amyloid
  Around wall of endoneurial microvessel   Asymmetric deposits

From: R Schmidt

From: R Schmidt

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From: R Schmidt

Amyloid
  Replaces basal lamina of endoneurial microvessel
  Surrounds endoneurial microvessel

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From: J Karamchandani

Amyloid: Fibrils

From: R Schmidt

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Amyloid: TTR Val30Met mutation

Nerve

H&E stain

Amyloid: Amorphous clusters in endoneurium

H&E stain

H&E stain

Amyloid: Amorphous, rounded clusters in endoneurium

Gomori trichrome stain

VvG stain

Toluidine blue stain

Amyloid
  Amorphous, rounded clusters in endoneurium
  Amyloid surrounded by pale cell-free regions

Toluidine blue stain

Congo red stain

Amyloid
  Amorphous, rounded clusters in endoneurium
  Perineurial deposition, scattered

Congo red stain

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Amyloid
  Surrounds endoneurial microvessel

Congo red stain

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Amyloid (TTR Val30Met): Muscle

H& E stain

Chronic denervation & Reinnervation, Progressive
  Grouped atrophy
  Larger muscle fibers are hypertrophied

VvG stain

ATPase pH 9.4 stain

Chronic denervation & Reinnervation, Progressive
  Fiber type grouping

ATPase pH 4.3 stain

ATPase pH 4.3 stain

Chronic denervation & Reinnervation, Progressive
  Muscle fibers in region of grouped atrophy
    Varied degrees of immaturity (Type 2C)
    Esterase positive cytoplasm

Esterase stain

Congo red stain

Amyloid deposits
  Most prominent in smaller perimysial vessels

Congo red stain

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Amyloid (TTR Thr60Ala): Muscle

H&E stain

Congo red stain

Amyloid deposits
  Most prominent in connective tisue & around muscle fibers

Congo red stain

Congo red stain

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8/30/2025