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. 2009 Jul;68(7):774-84.
doi: 10.1097/NEN.0b013e3181aacbe9.

Brains with medial temporal lobe neurofibrillary tangles but no neuritic amyloid plaques are a diagnostic dilemma but may have pathogenetic aspects distinct from Alzheimer disease

Peter T Nelson  1 , Erin L Abner, Frederick A Schmitt, Richard J Kryscio, Gregory A Jicha, Karen Santacruz, Charles D Smith, Ela Patel, William R Markesbery
Affiliations

Brains with medial temporal lobe neurofibrillary tangles but no neuritic amyloid plaques are a diagnostic dilemma but may have pathogenetic aspects distinct from Alzheimer disease

Peter T Nelson et al. J Neuropathol Exp Neurol. 2009 Jul.

Abstract

Brains that have many neurofibrillary tangles (NFTs) in medial temporal lobe structures (Braak stage III or IV) but no cortical neuritic plaques (NPs) may be a diagnostic dilemma; they also raise questions about the amyloid cascade hypothesis of Alzheimer disease (AD) in which NFT development is thought to occur downstream of the development of amyloid plaques. To determine the clinical, demographic, and biological factors related to NFT+/NP- cases, we analyzed 26 NFT+/NP- patient brains identified from the University of Kentucky AD Center autopsy cohort (n=502); most of these patients were at least 85 years old and lacked profound antemortem cognitive impairment. A subset of the cases had NFTs in the medulla oblongata. Aberrant trans-activator regulatory DNA-binding protein 43 immunohistochemical staining was seen in 5 of the 26 cases with the clinical diagnoses of AD or mild cognitive impairment. We also queried cases in the National Alzheimer's Coordinating Center Registry (n=5,108) and found 219 NFT+/NP- cases. Those patients had a relatively high likelihood of belonging to a birth cohort with the highest incidence of influenza infection during the 1918 to 1919 pandemic. This observation may link the pathogenesis in NFT+/NP- cases to encephalitis during childhood. We conclude that NFT+/NP- cases comprise approximately 5% of aged individuals in multiple data sets; these cases are not necessarily within the spectrum of AD.

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Figures

Figure 1
Figure 1
Data from the University of Kentucky Alzheimer Disease Center (A, B) and the Nun Study (C, D) indicate that neurofibrillary tangles (NFTs) are seen in medial limbic structures (hippocampal formation and amygdala) without neuritic plaques (NPs) (B, D). By contrast they are rarely seen in isocortical areas without NPs (A, C). The case with a few NPs and cortical NFTs (orange arrow in A) also had chronic bilateral cortical contusions. Isocortical lesion counts are totals from parietal, occipital, temporal, and frontal cortex; medial limbic lesion counts refer to CA1, subiculum, amygdala, and entorhinal cortex. Cases with few NPs but with isocortical NFTs are indicated by a red arrow in A; cases with few NPs but with medial limbic NFTs are indicated by a green arrow in B.
Figure 2
Figure 2
Neuropathologic features of neurofibrillary tangle (NFT)-positive/Neuritic plaque (NP)-negative cases from the University of Kentucky Alzheimer Disease Center. (A) Low-power section from CA1 of the hippocampus shows a low neuronal density but insufficient cell loss for the diagnosis of hippocampal sclerosis. (B) Preservation of neurons and NFTs is evident at higher magnification. (C) There are many NFTs in CA1 demonstrated by silver impregnation. (D) A case stained for amyloid A-β peptide with NPs shows focal cerebral amyloid angiopathy (red arrow) but no extracellular parenchymal NPs. (E, F) Amyloid NPs are evident in the hippocampus In an AD case (green arrows, E) but only NFTs are present in the amygdala in an NFT+/NP− case (F). Scale bars: A, D = 1 mm; B = 100 µm; C, E, F = 50 µm. A, B = Hematoxylin and eosin; C, E, F, Gallyas silver impregnation; D, immunohistochemistry.
Figure 3
Figure 3
Neurofibrillary pathology in the ventral medial medulla oblongata in a neurofibrillary tangle (NFT)-positive/neuritic plaque (NP)-negative case. (A) Diagram indicates the area with aberrant phospho-tau (PHF-1) immunoreactivity and Gallyas silver staining in red cross-hatching. (B) Low-power photomicrograph shows the distribution of PHF-1-immunoreactive cells (brown) on either side of the midline (blue asterisk). (C) Higher power demonstrates that the cells have the morphologic appearance of glial tangles. Scale bars: B = 100 µm; C = 20 µm.
Figure 4
Figure 4
Relative proportions of Neurofibrillary tangle (NFT)-positive/Neuritic plaque (NP)- negative (NFT+/NP−) cases (n = 212 between 1900 and 1930) and combined cases from National Alzheimer’s Coordinating Center from Braak stage III/IV and CERAD “definite,” or Braak stage 0 CERAD “negative”; n = 418) (controls [Ctrl]) by birth year. The NFT+/NP− cases tend to have a significantly different distribution (p < 0.001 by the Kolmogorov-Smirnov statistic) with an apparent peak in the years 1911–1912. The birth cohort with peak incidence of the 1918–1919 influenza pandemic is indicated by a green line.
Figure 5
Figure 5
Hypothesis on the pathogenesis of neurofibrillary tangle (NFT)-positive/neuritic plaque (NP)-negative cases. Post-encephalitic parkinsonism (PEP) is a progressive neurodegenerative disease caused by encephalitis lethargica and linked to the 1918–1919 influenza pandemic that affected up to 40% of many Western populations. The brains of PEP patients may have hippocampal NFTs without NPs. PEP incidence peaked by the early 1950s (purple line) but it is not known what happened to individuals who were affected by influenza and/or encephalitis lethargica prior to 1920 but did not develop PEP. We hypothesize that in some patients with a milder prodrome and/or different host factors there was a longer subclinical phase (orange line) and that the disease was became manifest as many NFTs in medial temporal lobe structures. Patients that were not otherwise destined to develop Alzheimer disease did not develop NPs. If this hypothesis is valid, the incidence of NFT+/NP− cases would decline as this birth cohort passes.
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References

    1. Armstrong RA. Plaques and tangles and the pathogenesis of Alzheimer's disease. Folia Neuropathol. 2006;44:1–11. - PubMed
    1. Castellani RJ, Lee HG, Zhu X, et al. Alzheimer disease pathology as a host response. J Neuropathol Exp Neurol. 2008;67:523–531. - PMC - PubMed
    1. Nelson PT, Braak H, Markesbery WR. Neuropathology and cognitive impairment in Alzheimer’s disease: A complex but coherent relationship. J Neuropathol Exp Neurol. 2009;68:1–14. - PMC - PubMed
    1. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–259. - PubMed
    1. Braak H, Braak E. Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol Aging. 1995;16:271–278. discussion 8–84. - PubMed

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