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Objectives: Frontotemporal dementia (FTD), the second commonest degenerative cause of dementia under the age of 65, often presents with striking changes in behaviour and personality in association with frontal lobe atrophy. Based on the behavioural changes observed in FTD, it is commonly assumed that the orbitofrontal cortex is the earliest and most severely affected frontal sub-region. However, evidence to support this assumption has to date been largely lacking. Methods: Using a novel volumetric MRI method, we performed a detailed volumetric analysis of six frontal regions in 12 subjects with the frontal or behavioural variant of FTD (fvFTD) and 12 age-, education- and sex-matched normal controls. The regions studied were: the orbitofrontal and insula regions (representing the orbitobasal cortex); the inferior and middle frontal regions (representing the dorsolateral prefrontal areas); and the superior frontal and anterior cingulate regions (representing the medial prefrontal areas). Results: As a group, the fvFTD patients showed atrophy involving all six regions. We then segregated the 12 patients into three sub-groups according to their overall degree of atrophy. In the mildest group (n = 3) all regions fell within 2 standard deviations of normal. In the intermediate group (n = 6) only the orbitofrontal region (bilaterally) fell clearly outside the control range (>2 z scores below the control mean); the next most atrophic region in this group was the right insular region. The severe group (n = 3) had generalized atrophy throughout the frontal regions measured. Conclusions: In conclusion, patients with the earliest stages of fvFTD show no significant loss of volume in any frontal lobe area as measured by a novel MRI volumetric technique. When volume loss does occur, changes are initially seen in the orbitofrontal cortex before atrophy becomes more widespread. These results provide some partial support for the often-quoted assumption that the orbitofrontal cortex is the locus of earliest pathology in fvFTD, although these findings must be regarded as preliminary in view of the small numbers of patients involved. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]