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BRIEF COMMUNICATIONS: K. J. Hatanpaa, D. M. Blass, O. Pletnikova, B. J. Crain, E. H. Bigio, J. C. Hedreen, C. L. White, III, and J. C. Troncoso Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia Neurology 2004; 63: 538-542 [Abstract] [Full text] [PDF]

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Reply to Honig et al

Kimmo J Hatanpaa, Juan C. Troncoso   (23 November 2004)

Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia

Lawrence S. Honig, Nikolaos Scarmeas   (23 November 2004)

Reply to Honig et al 23 November 2004
Kimmo J Hatanpaa, University of Texas Southwestern Medical School Department of Pathology, 5323 Harry Hines Blvd., Rm. H2.130, Dallas, TX, Juan C. Troncoso Send Correspondence to journal: Re: Reply to Honig et al Kimmo.Hatanpaa{at}UTSouthwestern.edu Kimmo J Hatanpaa, et al.	We appreciate this opportunity to clarify the issue of coexisting pathology in our cases originally classified as hippocampal sclerosis dementia.[1] Nine of the 18 cases showed no neocortical Alzheimer pathology (tangles or neuritic plaques). Among the remaining nine cases, there were seven cases that had either rare tangles and no neuritic plaques or no tangles and rare neuritic plaques in the neocortex, which are insufficient findings to explain dementia. One of the remaining two cases (H14) showed sparse to moderate neocortical neuritic plaques (CERAD age- related plaque score A or B) and sparse tangles limited to the entorhinal cortex only. This case also showed ubiquitinated, tau-negative inclusions (MND inclusions) in the dentate gyrus. This patient’s dementia is probably best attributed to the motor neuron disease inclusion dementia (MNDID) variant of FTD and not to the relatively mild Alzheimer pathology. The remaining one case (H15) showed sparse neuritic plaques (CERAD plaque score A) and rare tangles in the neocortex, whereas frequent tangles were found in the entorhinal cortex. There were no definitive MND inclusions in the dentate gyrus, although this was difficult to evaluate due to the presence of occasional tangles in the dentate gyrus. It is possible that the Alzheimer pathology, although relatively mild, contributed to this patient’s dementia. With the possible exception of a single case, Alzheimer pathology probably did not contribute to these patients’ dementia, regardless of whether MND inclusions were present. Aside from this, we agree with Drs. Honig and Scarmeas that cases with disparate numbers of tangles and neuritic plaques can be difficult to classify. Our recommendation is to resist the temptation to assign a definitive cause of dementia to every case. Of note, the presence of neuritic plaques without any tangles in the neocortex is often not associated with cognitive impairment, whereas the presence of both tangles and neuritic plaques almost always is.[6, 7] References [6] Troncoso JC, Martin LJ, Dal Forno G, Kawas CH. Neuropathology in controls and demented subjects from the Baltimore Longitudinal Study of Aging. Neurobiol Aging 1996;17:365-71. PMID: 8725897. [7] Schmitt FA, Davis DG, Wekstein DR, Smith CD, Ashford JW, Markesbery WR. "Preclinical" AD revisited: neuropathology of cognitively normal older adults. Neurology 2000;55:370-6. PID: 10932270.
Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia 23 November 2004
Lawrence S. Honig, Columbia University College of Physicians & Surgeons 630 West 168th St. (P&S Unit 16), New York, NY 10032-3795, Nikolaos Scarmeas Send Correspondence to journal: Re: Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia lh456{at}columbia.edu Lawrence S. Honig, et al.	Two recent articles on hippocampal sclerosis dementia (HSD)[1,2], suggest that this disorder may represent a frontotemporal dementia (FTD). As the authors state, HSD has long been a mysterious entity, both clinically due to lack of a characteristic syndrome, and pathologically, due to absence of a specific uniform pathological signature other than hippocampal neuronal loss and gliosis. Disparate findings with regard to pathologic prevalence of the disorder and presence of concomitant neuropathological findings further complicate our understanding. Hypotheses include: (a) HSD, which often co-exists with Alzheimer’s disease (AD) or vascular disease (VaD), may be an uncommon accompaniment of various disorders; (b) HSD is a unique degenerative dementia; and (c) HSD is a frontotemporal dementia. Subsuming HSD into the FTD superfamily would be favored by its localization to mesial temporal lobes, the findings that reexamination of 18 cases of “pure” HSD show 11 (61%) have ubiquitin-positive tau-negative inclusions in dentate gyrus[1], and the fact that similar but presumably molecularly-nonspecific findings are seen in “motor neuron dementia” (whether clinical motor neuron disease is present or absent). However, before categorizing nearly all HSD as FTD, ascertainment of the degree of coexisting pathology in the authors’ cases is relevant. The authors state their cases did not met NIA-Reagan (NIAR)[3] criteria for “high” or “intermediate” likelihood AD. However, among the drawbacks of the NIAR criteria[3] is that brains with plentiful neuritic plaques but without neurofibrillary pathology, or vice versa, are nonclassifiable (also problematic in cases with Lewy Body involvement). Prior reports [4,5] have noted that many HSD cases have significant coexisting plaque (scores B or C) and tangle (Braak stages III – V) burden and prevalence of ‘pure’ HSD cases is significantly diminished if strict requirements for absence of other AD-type pathology are applied. (For example, Leverenz et al [5] found 8% cases with “pure HS”, but only 2% were still “pure” with more restrictive requirements for exclusion of AD changes.) Thus, interpretation of these new reports[1,2] would be aided by greater knowledge of the neuritic plaque and tangle burdens, and whether there was differentially increased distribution of AD markers particularly in those cases without ubiquitinated inclusions. If there are different etiologies of HSD, then perhaps these new cases, with average age at onset 68 (range 49-87)[1], lower than that of others (e.g. 80, range 66 to 90)[5], may represent a group of HSD enriched for the “FTD type,” rather than for the “AD type”. References 1) Hatanpaa KJ, Blass DM, Pletnikova O, et al.: Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia. Neurology 2004; 63:538-542. PMID: 15304590. 2) Blass DM, Hatanpaa KJ, Brandt J, et al.: Dementia in hippocampal sclerosis resembles frontotemporal dementia more than Alzheimer disease. Neurology 2004; 63:492-497. PMID: 15304580. 3) The National Institute on Aging and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease: Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. Neurobiology of Aging 1997; 18:S1-2. PMID: 9330978. 4) Ala TA, Beh GO, Frey WH, 2nd: Pure hippocampal sclerosis: a rare cause of dementia mimicking Alzheimer's disease. Neurology 2000; 54:843- 848. PMID: 10690974. 5) Leverenz JB, Agustin CM, Tsuang D, et al.: Clinical and neuropathological characteristics of hippocampal sclerosis: a community- based study. Arch Neurol 2002; 59:1099-1106. PMID: 12117357.