Comment on Viewpoint Article - Con: Can neuropathology really confirm the exact diagnosis of dementia? Kurt Jellinger, Institute of Clinical Neurobiology 28 June 2010 Analysing 1,677 cases with antemortem diagnosis of dementia from the National Alzheimer's Coordination Registry, Nelson et al  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  "plaque-intensive" type may be similar to the "hippocampal" type of AD (neuritic Braak stages III/IV) with frequent neuritic plaques , 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 . Like the TDD patients, this group often lacked profound antemortem cognitive impairment (last MMSE scores 14-30 , 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  demented cohort approximated those of severe AD. Despite these deviations concerning "atypical" AD cases, together with Nelson et al  one can conclude that consideration of the impact of frequent "mixed pathology" in aged persons in the diagnostic challenge , 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 3. Jellinger KA, Attems J: Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease. Acta Neuropathol 2007, 113:107-117. 4. Bancher C, Jellinger KA: Neurofibrillary tangle predominant form of senile dementia of Alzheimer type: a rare subtype in very old subjects. Acta Neuropathol 1994, 88:565-570. 5. Terry RD, Hansen LA, DeTeresa R, Davies P, Tobias H, Katzman R: Senile dementia of the Alzheimer type without neocortical neurofibrillary tangles. J Neuropathol Exp Neurol 1987, 46:262-268. 6. Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J: The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology 2004, 62:1984-1989. 7. Jellinger KA: Criteria for the neuropathological diagnosis of dementing disorders: routes out of the swamp? Acta Neuropathol 2009, 117:101-110. 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.