National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach

Abstract

We present a practical guide for the implementation of recently revised National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an "ABC" score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.

Figure 1. “ABC” Score for Alzheimer’s Disease Neuropathologic Change

Immunohistochemical detection of Aβ plaques in (a) neocortex with as an example of “A1”, (b) neostriatum as an example of “A2”, and (c) molecular layer of cerebellum as an example of “A3”. Scale bars are 500 microns. Anti-Aβ was antibody 6F/3D (Novocastra, Newcastle, United Kingdom).

Figure 2. “ABC” Score for Alzheimer’s Disease Neuropathologic Change

Immunohistochemical detection of neurofibrillary degeneration using phospho-tau antibody in the occipital cortex (Brodmann areas 17 and 18) as an example of “B3”. Scale bars equal (a) 150 microns and (b) 100 microns. PHF-1 antibody was generously provided by Dr. Peter Davies.

Figure 3. “ABC” Score for Alzheimer’s Disease Neuropathologic Change

Bielschowsky stain of neocortex shows (a) diffuse plaques but not neuritic plaques as an example of “C0”, and increasing density of neuritic plaques as examples of (b) “C1” (1 to 5 neuritic plaques per 1 mm²), (c) “C2” (> 6 but < 20 neuritic plaques per 1 mm²), and (d) “C3” (> 20 neuritic plaques per 1 mm²). Scale bars equal 100 microns.

Figure 4. Lewy Body Disease Classification

Immunohistochemical detection of α-synuclein in (a, scale bar 250 microns) dorsal motor nucleus of the vagus nerve and (b, scale bar 125 microns) substantia nigra neurons as examples of “Brainstem-predominant LBD”, (c, scale bar 50 microns) amygdala as an example of “Amygdala-predominant LBD”, (d, scale bar = 200 microns) anterior cingulate gyrus as an example of “Limbic (Transitional) LBD”, and (e - h, scale bar = 100 microns) superior temporal gyrus as an example of “Neocortical (diffuse) LBD” with varying levels of LBD severity: mild (e), moderate (f), severe (g), and very severe (h) [38]. Anti-alpha-synuclein was antibody KM51 (Novocastra, Newcastle, United Kingdom).

Figure 5. Microvascular Lesion

Cerebral cortex stained with (a) hematoxylin and eosin or for (b) immunohistochemical detection of glial fibrillary acidic protein reveals a microvascular lesion (MVL). Scale bar = 500 microns. Anti-GFAP was antibody 6F2 (DAKO, Glostrup, Denmark).

Figure 6. TDP-43 Inclusions

Immunohistochemical detection of TDP-43 in the dentate gyrus in a subject (a) without hippocampal sclerosis or (b) another case with hippocampal sclerosis that shows cytoplasmic inclusions in granule neurons that are (c) further highlighted by phospho-TDP-43. Scale bars equal 50 microns. Anti-TDP-43 was antibody 10782-2-AP (ProteinTech, Chicago IL, USA). Anti-phospho-TDP-43 was antibody TIP-PTD-M01 (pS409/410-1 from Cosmo Bio, Tokyo, Japan).