Braak staging of Alzheimer's disease

Introduction

Braak & Braak define 2 separate staging criteria for neuropathologic staging of Alzheimer's disease.

Staging

staging based on PHF-tau pathology

Braak staging of Alzheimer's disease based upon histopathology of neurofibrillary tangles & neuropil threads in autopsy specimens.

The distribution & packing density of amyloid plaques varies widely & is of little significance for differentiation of neuropathologic stages.

6 stages distinguished by location & severity of changes see 'NFT & neuropil thread by stage & region (Braak & Braak)'

• trans-entorhinal stages 1-2: clinically silent
  • involvement confined to transentorhinal layer pre-alpha
• limbic stages 3-4: incipient AD
  • involvement of CA1
• neocortical stages 5-6: fully developed AD
  • involvement of all areas of association cortex

* microglial activation & PHF-tau propagate jointly across Braak stages

staging based on beta-amyloid pathology

Most amyloid plaques are not associated with neurofibrillary changes & neurons within the amyloid appear normal.

In early stages of Alzheimer's disease, amyloid plaques show considerable variability in shape, size & quantity.

End-stage Alzheimer's disease shows a fairly consistent distribution pattern of amyloid plaques.

3 stages of amyloid deposition are described

• stage 1:
  • low densities of amyloid in the neocortex, especially the basal part of frontal lobe, temporal lobe & occipital lobe
  • the hippocampus is free of amyloid
  • the parvocellular layer of the presubiculum & the entorhinal cortex layers pre-beta & pre-gamma show weakly- staining bands of amyloid

• stage 2:
  • medium densities of amyloid deposits are present in all areas of association cortex
  • only the primary sensory cortex & primary motor cortex remain free of amyloid
  • all layers of the cortex are are are affected; only the external glial layer remains free of amyloid
  • regions of white matter underlying the cortex show small, condensed deposits of amyloid.

• the hippocampus has limited amyloid deposition
• a few globular deposits of amyloid are restricted to the pyramidal layers of the CA1 & subiculum
• additionally, densely packed rows of amyloid occur in the molecular layer of the subiculum extending into the stratum radiatum of CA1 & the molecular layer of the dentate gyrus

• the parvocellular layer of the presubiculum is filled with diffusely distributed amyloid
• bands of amyloid may be seen in the entorhinal cortex

• stage 3:
  • virtually all areas of the cortex are involved including primary sensory cortex & primary motor cortex
  • the hippocampus shows relatively few deposits
  • gradual involvement of subcortical regions occurs
  • the striatum, thalamus, hypothalamus, subthalamus & red nucleus show deposits
  • the molecular layer of the cerebellum may contain patches of amyloid
  • the substantia nigra remains free of amyloid

More general terms

• histopathology of Alzheimer's disease
• staging of Alzheimer's disease