Comment on Viewpoint Article - Con: Can neuropathology really confirm the exact diagnosis of dementia?

Kurt Jellinger   (2010-06-28 10:39)  Institute of Clinical Neurobiology

Analysing 1,677 cases with antemortem diagnosis of dementia from the National Alzheimer's Coordination Registry, Nelson et al [1] recently commented on those cases that fall outside the National Institute on Aging and Reagan Institute (NIA-RI) recommendations. 82.4% fell into diagnostic "boxes" within the rubric of the consensus recommendations. Two specific categories were considered: (1) "tangle-intensive" cases with the highest density of neurofibrillary tangles but only moderate density of neuritic plaques (9.4% of the overall) were considered more likely to be designated as "high likelyhood" that dementia was due to AD, whereas (2) "plaque-intensive" patients with high density of amyloid plaques and intermediary severity tangles (6.0% of total) were typically designated as "intermediate likelyhood". Unfortunately, both these categories appear not to be identical with the "tangle-dominant" type (TDD) (with 3- and 4-repeat tau pathology similar to NFTs in "classical" AD but often restricted to the limbic system, absence of neuritic plaques and no or very little amyloidosis) accouting for 5-7% of oldest-old demented [2-4], and the "plaque-predominant" type with abundant amyloid plaques, no or very little neuritic pathology restricted to the limbic system and lacking overt tangle formation, accounting for 3.5-8% of demented subjects aged 85+ years [5-7]. While Nelson et al's [1] "plaque-intensive" type may be similar to the "hippocampal" type of AD (neuritic Braak stages III/IV) with frequent neuritic plaques [8], the TDD phenotype appears to correspond to a recently described form with medial temporal lobe neurofibrillary tangles but no neuritic plaques accounting for 5.2% of an autopsy cohort of 502 elderly persons suggested to have pathogenetic aspects from AD [9]. Like the TDD patients, this group often lacked profound antemortem cognitive impairment (last MMSE scores 14-30 [9], while TDD patients had only mildly increased final MMSE scores compared to "classical" AD (mean 9.0 vs. 2.0) [2, 3], and "tangle-intensive" cases (Braak stage VI) encompassing 1.3% of Nelson et al's [1] demented cohort approximated those of severe AD. Despite these deviations concerning "atypical" AD cases, together with Nelson et al [1] one can conclude that consideration of the impact of frequent "mixed pathology" in aged persons in the diagnostic challenge [10], more exact categories and a better understanding of the pathology of early phases of the disease may be helpful for guiding neuropathologists in the diagnosis of AD.

References:
1. Nelson PT, Kukull WA, Frosch MP: Thinking outside the box: Alzheimer-type neuropathology that does not map directly onto current consensus recommendations. J Neuropathol Exp Neurol 2010, 69:449-454.
2. Jellinger KA, Attems J: Tangle dominant dementia. In Neuroscience Research Advances. Edited by Figueredo B, Meléndez F. Hauppauge, NY: Nova Science Publishers; 2009: 135-155
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8. Mizutani T, Amano N, Sasaki H, Morimatsu Y, Mori H, Yoshimura M, Yamanouchi H, Hayakawa K, Shimada H: Senile dementia of Alzheimer type characterized by laminar neuronal loss exclusively in the hippocampus, parahippocampus and medial occipitotemporal cortex. Acta Neuropathol 1990, 80:575-580.
9. Nelson PT, Abner EL, Schmitt FA, Kryscio RJ, Jicha GA, Santacruz K, Smith CD, Patel E, Markesbery WR: 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. J Neuropathol Exp Neurol 2009, 68:774-784.
10. Jellinger KA, Attems J: Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol 2010, 119:421-433.

Competing interests

No competing interests.

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