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  1. 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 [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.

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    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.
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    Competing interests

    No competing interests.