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Differential clinicopathologic and genetic features of late-onset amnestic dementias

2014; Springer Science+Business Media; Volume: 128; Issue: 3 Linguagem: Inglês

10.1007/s00401-014-1302-2

1432-0533

Melissa E. Murray, Ashley Cannon, Neill R. Graff‐Radford, Amanda M. Liesinger, Nicola J. Rutherford, Owen A. Ross, Ranjan Duara, Minerva M. Carrasquillo, Rosa Rademakers, Dennis W. Dickson,

Dementia and Cognitive Impairment Research

Hippocampal sclerosis of the elderly (HpScl) and Alzheimer's disease (AD), especially the limbic-predominant subtype (LP-AD), are amnestic syndromes that can be difficult to distinguish. To complicate matters, a subset has concomitant HpScl and AD (HpScl-AD). We examined a large cohort of autopsy-confirmed cases of HpScl, HpScl-AD, LP-AD, and typical AD to identify distinct clinical, genetic, and pathologic characteristics. HpScl cases were significantly older at death and had a substantially slower rate of cognitive decline than the AD subtypes. Genetic analysis revealed that the AD groups (AD, LP-AD, and HpScl–AD) were more likely to be APOE ε4 carriers. In contrast, the HpScl groups (HpScl and HpScl-AD) were more likely to exhibit genetic variants in GRN and TMEM106B that are associated with frontotemporal lobar degeneration. The HpScl groups had a high frequency of TDP-43 pathology that was most often Type A morphology and distribution, while typical AD and LP-AD had a significantly lower frequency of TDP-43 pathology that was most often Type B. These results suggest that HpScl and AD are pathologically and genetically distinct and non-synergistic neurodegenerative processes that present with amnestic dementia. Pure HpScl and HpScl with concomitant AD occur most often in elderly individuals.