Subcortical and deep cortical atrophy in Frontotemporal Lobar Degeneration

https://doi.org/10.1016/j.neurobiolaging.2009.05.004Get rights and content

Abstract

Though neuroimaging, pathology and pathophysiology suggest a subcortical and deep cortical involvement in Frontotemporal Lobar Degeneration (FTLD), no studies have comprehensively assessed the associated gray matter (GM) volume changes. We measured caudate, putamen, thalamus, and amygdala GM volume using probabilistic a-priori regions of interest (ROIs) in 53 early FTLD patients (38 behavioral variant FTD [bvFTD], 9 Semantic Dementia [SD], 6 Progressive Non-Fluent Aphasia [PNFA]), and 25 age-matched healthy controls (HC). ANOVA showed significant (P < 0.001) main effect of diagnosis, and significant interactions for diagnosis and region, and diagnosis and hemisphere. Post-hoc comparisons with HC showed bilateral GM atrophy in the caudate, putamen and thalamus, in bvFTD; a left-confined GM reduction in the amygdala in SD; and bilateral GM atrophy in the caudate and thalamus, and left-sided GM reduction in the putamen and amygdala in PNFA. Correlation analyses suggested an association between GM volumes and language, psychomotor speed and behavioral disturbances.

This study showed a widespread involvement of subcortical and deep cortical GM in early FTLD with patterns specific for clinical entity.

Introduction

Frontotemporal Lobar Degeneration (FTLD), the commonest cause for dementia after Alzheimer's disease, refers to a complex neurodegenerative disorder primarily characterized by atrophy in the frontal lobes and the anterior portions of the temporal lobes. FTLD includes clinically, anatomically and genetically heterogeneous conditions, presenting mostly with personality changes and/or cognitive deficits, in particular language and executive functions. Three main clinical entities have been described, as the behavioral variant FTD (bvFTD), Semantic Dementia (SD), and Progressive Non-Fluent Aphasia (PNFA) (McKhann et al., 2001, Neary et al., 1998).

Specifically, each entity is characterized by a separate and distinguishing pattern of cortical gray and white matter atrophy, as revealed by previous neuroimaging studies (Borroni et al., 2007, Gorno-Tempini et al., 2004).

Notwithstanding, neuropathologic investigations showed a subcortical involvement, with different degrees of atrophy and mild astrocytosis being present throughout caudate, putamen, pallidus, and amygdala (Hodges and Miller, 2001, Munoz et al., 2003, Yancopoulou et al., 2005).

Furthermore, the frontal-subcortical circuitry has been well described: the orbitofrontal cortex (OFC) projects extensively to and forms feedback loops with subcortical structures such as the basal ganglia and limbic regions, particularly the amygdala (Kringelbach and Rolls, 2004).

Thus, the subcortical and deep cortical structures may provide important clues on the clinical expression of this disorder, including also cognitive and behavioral abnormalities, given the growing consensus on the involvement of the basal ganglia in non-motor functions such as language, executive functions, memory, and learning (Graybiel, 2005).

To date, no studies have comprehensively assessed the subcortical and deep cortical gray matter (GM) volume changes in FTLD, taking also the amygdala into account. To investigate it in an objective, quantitative way, and in a large subjects’ sample, we performed a fully-automated volumetric analysis using regions of interest (ROIs) based on recently developed probabilistic atlases (Eickhoff et al., 2005, Mazziotta et al., 2001). These atlases are based on the anatomical examination of large samples of healthy subjects and provide information about the voxel specific probability for observing a given structure in stereotactic space. Probabilistic maps are hence well suited not only as a reference for the allocation of functional imaging results but can also provide a-priori information about location and individual variability in volumetric investigations (Eickhoff et al., 2006, Hammers et al., 2003).

We measured gray matter (GM) volumes of the caudate nucleus, putamen and thalamus, as well as the amygdala. We hypothesized that the clinical and behavioral differences among entities would be reflected by different patterns of subcortical changes, with selective involvement of anatomical structures, and with left-prevalent distribution in the language-variants (SD and PNFA).

Section snippets

Subjects

Patients who met the Neary and McKhann criteria for FTLD were consecutively recruited from March 2002 through December 2007 at the “Center for Aging Brain and Neurodegenerative Diseases”, University of Brescia, Italy (McKhann et al., 2001, Neary et al., 1998).

All patients underwent a general medical examination, a review of full medical history and routine laboratory screening before inclusion. The diagnostic assessment consisted of a full neurological examination, a semi-structured interview,

ROIs validation

The coefficient of similarity between the Manual ROIs and the MPM-ROIs are reported in Table 2. The high similarity measured (all coefficients are above 90%) for all regions and for all diagnostic group support the reliability of the GM volume estimation obtained with the fully-automated MPM-ROIs.

ROIs group comparisons

Mean GM volumes as measured in the different diagnostic groups are summarised in Table 3. ANOVA analysis showed significant main effect for diagnosis (F = 56.49, P < 0.001), brain structure (F = 115.01, P < 

Subcortical and deep cortical GM atrophy in FTLD

In this work, we aimed at evaluating the atrophy of the basal ganglia and deep cortical grey matter in FTLD patients by using in-vivo volumetric analysis, irrespective of the cortical involvement, already well characterized in previous neuroimaging studies (Borroni et al., 2007, Gorno-Tempini et al., 2004).

We found a specific pattern of atrophy in each FTLD phenotype, suggesting a role of these regions in contributing to FTLD signs and symptoms.

We found, in particular, a bilateral basal ganglia

Conclusion

The study yielded a comprehensive description of the differential involvement of subcortical and deep cortical structures and their relation to neuropsychological measures and clinical presentation in FTLD. Moreover, our data further support the view that subcortical structures play a relevant role in a wide spectrum of cognitive and behavioral functions.

Conflict of interest

None.

Acknowledgements

The authors wish to thank the patients and their families for taking part into this study. The authors are indebted to the staff of the Neurology Unit, Brescia Hospital for accommodating the study.

This work was financially supported by EULO (Ente Universitario Lombardia Orientale), and DIMI (Diagnostic Molecular Imaging). Sixth European Program, Project No: LSHB-CT-2005-512146.

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