Distinct antemortem profiles in patients with pathologically defined frontotemporal dementia.
ABSTRACT Clinical-pathologic studies are crucial to understanding brain-behavior relations and improving diagnostic accuracy in neurodegenerative diseases.
To establish clinical, neuropsychological, and imaging features of clinically diagnosed patients with frontotemporal dementia (FTD) that help discriminate between pathologically determined tau-positive FTD, tau-negative FTD, and frontal-variant Alzheimer disease.
Retrospective clinical-pathologic survey.
Academic medical center. Patients Sixty-one participants with the clinical diagnosis of a frontotemporal spectrum disorder who underwent a neuropsychological evaluation and had an autopsy-confirmed disease.
Neuropsychological performance and high-resolution structural magnetic resonance imaging (MRI).
Distinguishing features of patients with tau-positive FTD include visual perceptual-spatial difficulty and an extrapyramidal disorder significantly more often than other patients, significant cortical atrophy in the frontal and parietal regions as evidenced on MRI, and the burden of pathology is greatest in the frontal and parietal regions. Patients with tau-negative FTD are distinguished by their greater difficulties with social, language, and verbally mediated executive functions, significant cortical atrophy in the frontal and temporal regions as evidenced on MRI, and significant frontal and temporal pathology. Patients with Alzheimer disease at autopsy have significantly impaired delayed recall during episodic memory testing; atrophy that involves temporal areas, including the hippocampus, as evidenced on MRI; and widely distributed pathology including the medial temporal structures. A discriminant function analysis grouped patients on the basis of clinical and neuropsychological features with 87.5% accuracy.
Clinical, neuropsychological, and imaging profiles can contribute to accurate antemortem diagnosis in FTD.
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ABSTRACT: Paired helical filaments (PHFs) are prominent components of Alzheimer disease (AD) neurofibrillary tangles (NFTs). Rather than isolating NFTs, we selected for PHF populations that can be extracted from AD brain homogenates. About 50% of PHF immunoreactivity can be obtained in 27,200 x g supernatants following homogenization in buffers containing 0.8 M NaCl. We further enriched for PHFs by taking advantage of their insolubility in the presence of zwitterionic detergents and 2-mercaptoethanol, removal of aggregates by filtration through 0.45-microns filters, and sucrose density centrifugation. PHF-enriched fractions contained two to five proteins of 57-68 kDa that displayed the same antigenic properties as PHFs. Since the 57- to 68-kDa PHF proteins are antigenically related to tau proteins, they are similar to the tau proteins previously observed in NFTs. However, further analysis revealed that PHF-associated tau can be distinguished from normal, soluble tau by PHF antibodies that do not recognize human adult tau and by one- and two-dimensional PAGE.Proceedings of the National Academy of Sciences 09/1990; 87(15):5827-31. · 9.74 Impact Factor
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ABSTRACT: Ventromedial prefrontal cortex (VMF) damage can lead to impaired decision-making. This has been studied most intensively with the Iowa gambling task (IGT), a card game that asks subjects to overcome an initial attraction to high-payoff decks as losses begin to accrue. VMF subjects choose from the high risk decks more often than controls, but the fundamental impairments driving poor performance on this complex task have yet to be established. There is also conflicting evidence regarding the role of the dorsolateral prefrontal cortex (DLF) in this task. The present study examined whether poor performance on the IGT was specific for VMF damage and whether fundamental impairments in reversal learning contributed to IGT performance. We found that both VMF and DLF damage leads to impaired IGT performance. The impairment of VMF subjects, but not of DLF subjects, seems to be largely explained by an underlying reversal learning deficit.Cerebral Cortex 02/2005; 15(1):58-63. · 6.83 Impact Factor
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ABSTRACT: TDP-43 is a major ubiquitinated disease protein in the pathologic condition of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). To investigate the demographic, clinical, and neuropsychological features associated with subtypes of FTLD-U with TDP-43 inclusions (FTLD-U/TDP-43). Retrospective clinical-pathologic study. Academic medical center. Patients Twenty-three patients with histopathologically proven FTLD-U. Demographic, symptom, neuropsychological, and autopsy characteristics. There are notably different clinical and neuropsychological patterns of impairment in FTLD-U subtypes. Patients with FTLD-U/TDP-43 characterized by numerous neuronal intracytoplasmic inclusions have shorter survival; patients with FTLD-U/TDP-43 featuring numerous neurites have difficulty with object naming; and patients with FTLD-U/TDP-43 in whom neuronal intranuclear inclusions are present have substantial executive deficits. There are also different anatomical distributions of ubiquitin pathologic features in FTLD-U subgroups, consistent with their cognitive deficits. Distinct TDP-43 profiles may affect clinical phenotypes differentially in patients with FTLD-U.JAMA Neurology 11/2007; 64(10):1449-54. · 7.58 Impact Factor