First symptoms--frontotemporal dementia versus Alzheimer's disease.

Frontotemporal dementia (FTD) is often misdiagnosed as Alzheimer's disease (AD). We hypothesized that the first symptoms associated with FTD would be different from those seen in AD and that the first symptoms in FTD would reflect loss of function in the frontal region with the greatest degree of degeneration. The objective of the study was to compare the earliest symptoms in patients with FTD and AD, and to delineate the symptoms that were associated with right, left or bilateral frontotemporal degeneration in FTD. The first symptoms in 52 FTD and 101 AD patients were determined in retrospect. Based on functional imaging studies, the FTD patients were divided into those with predominantly bilateral (n = 15), left-sided (n = 19) and right-sided (n = 18) patterns of atrophy. The results showed that disinhibition, social awkwardness, passivity and loss of executive function were more common in FTD, while memory loss was more common in AD. Disinhibition was greatest in the asymmetric right-sided group, language dysfunction was commonest in the asymmetric left-sided group and loss of executive function was most frequent in the bilateral group. In summary, different first symptoms appeared in FTD and AD, which may help distinguish between the diseases. The anatomic site for FTD largely determined the kind of first symptoms.

Nuclear targeting of mutant Huntingtin increases toxicity.

Huntington's disease is a neurodegenerative disorder resulting from expansion of the polyglutamine region in huntingtin. Although huntingtin is normally cytoplasmic, in affected brain regions proteolytic fragments of mutant huntingtin containing the polyglutamine repeat form intranuclear inclusions. Here, we examine the contribution of nuclear localization to toxicity by transiently transfecting neuro-2a cells with an N-terminal huntingtin fragment similar in size to that believed to be present in patients. The huntingtin fragment, HD-N63, was targeted either to the cytoplasm with a nuclear export signal (NES) or to the nucleus with a nuclear localization signal (NLS). The NES decreased the number of cells with aggregates in the nucleus while an NLS had the opposite effect. By cotransfecting HD-N63 with GFP as a marker, we observed direct cell loss with constructs containing expanded polyglutamine repeats. Compared to unmodified HD-N63-75Q, adding an NES reduced cell loss by 57% while an NLS increased cell loss by 111%. These results indicate that nuclear localization of mutant huntingtin fragments plays an important role in cell toxicity.

Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins.

Atrophin-1 contains a polyglutamine repeat, expansion of which is responsible for dentatorubral and pallidoluysian atrophy (DRPLA). The normal function of atrophin-1 is unknown. We have identified five atrophin-1 interacting proteins (AIPs) which bind to atrophin-1 in the vicinity of the polyglutamine tract using the yeast two-hybrid system. Four of the interactions were confirmed using in vitro binding assays. All five interactors contained multiple WW domains. Two are novel. The AIPs can be divided into two distinct classes. AIP1 and AIP3/WWP3 are MAGUK-like multidomain proteins containing a number of protein-protein interaction modules, namely a guanylate kinase-like region, two WW domains, and multiple PDZ domains. AIP2/WWP2, AIP4, and AIP5/WWP1 are highly homologous, each having four WW domains and a HECT domain characteristic of ubiquitin ligases. These interactors are similar to recently isolated huntingtin-interacting proteins, suggesting possible commonality of function between two proteins responsible for very similar diseases.

Midline cerebral morphometry distinguishes frontotemporal dementia and Alzheimer's disease.

We investigated and contrasted midline cerebral structures in frontotemporal dementia (FTD) and Alzheimer's disease (AD). FTD and AD may be difficult to distinguish clinically. FTD typically affects frontal and anterior temporal regions, whereas AD tends to involve more posterior temporal and parietal areas. We hypothesized that disease-specific cerebral alterations would be differentially reflected in corresponding regions of the corpus callosum (CC), pericallosal CSF space (PCS), or their ratio (CC:PCS). Regions-of-interest (ROIs) from midsagittal MRIs in 17 AD, 16 FTD, and 12 elderly control (EC) subjects were analyzed. ROIs were divided into four regions using an anatomic landmark-based computer algorithm and were adjusted for head size variation. FTD subjects had a much smaller anterior CC region and significantly larger PCS area, particularly in anterior regions. AD and EC subjects did not differ significantly in any total or regional ROI measure. Total and anterior CC:PCS ratios were markedly lower in FTD patients. Across groups, total CC:PCS correlated significantly with midsagittal cerebral area and was similarly associated with Mini-Mental State Examination score. Anterior CC (AD) and PCS (FTD) regions exhibited disease-specific relationships to these variables. A discriminant model using two ROI variables correctly classified 91% of AD and FTD patients, comparing favorably with blind clinical MRI diagnostic ratings. Midline cerebral structural alterations reflect differential patterns of cerebral degeneration in AD and FTD, yielding morphometric indices that may facilitate the study of brain-behavior relationships and differential diagnosis of dementia.