Elsevier

Cortex

Volume 74, January 2016, Pages 149-157
Cortex

Behavioural neurology
Two insular regions are differentially involved in behavioral variant FTD and nonfluent/agrammatic variant PPA

https://doi.org/10.1016/j.cortex.2015.10.012Get rights and content

Abstract

The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) and the behavioral variant frontotemporal dementia (bvFTD) are focal neurodegenerative disorders belonging to the FTD-spectrum clinical syndromes. NfvPPA is characterized by effortful speech and/or agrammatism and left frontal atrophy, while bvFTD is characterized by social–emotional dysfunction often accompanied by right-lateralized frontal damage. Despite their contrasting clinical presentations, both disorders show prominent left anterior insula atrophy. We investigated differential patterns of insular sub-region atrophy in nfvPPA and bvFTD. Based on knowledge of insular connectivity and physiology, we hypothesized that the left superior precentral region of the dorsal anterior insula (SPGI) would be more atrophic in nvfPPA due to its critical role in motor speech, whereas the ventral anterior region would be more atrophied in bvFTD reflecting its known role in social–emotional–autonomic functions. Early stage nfvPPA and bvFTD patients matched for disease severity, age, gender and education and healthy controls participated in the study. Detailed clinical history, neurological examination, neuropsychological screening evaluation, and high-resolution T1-weighted brain magnetic resonance imaging (MRI) were collected. Voxel-based morphometry (VBM) was applied to perform group comparisons across the whole brain and in bilateral insula region of interest (ROI). Correlation analyses between insular sub-region atrophy and relevant clinical features were performed. Whole brain group comparisons between nfvPPA and bvFTD showed the expected predominantly left or right anterior insular atrophy pattern. ROI analysis of bilateral insula showed that the left SPGI was significantly more atrophied in nfvPPA compared to bvFTD, while the bilateral ventral anterior and right dorsal anterior insula sub-regions were more atrophied in bvFTD than nfvPPA.

Only left SPGI volume correlated with speech production abilities, while left and right ventral anterior insula volumes correlated with ratings of aberrant eating behavior.

These two FTD clinical variants show different patterns of insular sub-region atrophy in the left precentral dorsal anterior and bilateral ventral anterior regions, providing further evidence for the role of these sub-regions in speech production and social–emotional function.

Introduction

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative diseases characterized by atrophy of frontal, temporal, and insular brain regions. Clinically, FTD manifests either with prominent behavioral and personality changes (behavioral variant, bvFTD; Neary et al., 1998, Rascovsky et al., 2011) or with isolated language impairments (primary progressive aphasia, PPA; Mesulam, 1982, Mesulam, 2001).

The non-fluent/agrammatic variant PPA (nfvPPA) is characterized by agrammatism and/or effortful, halting speech consistent with apraxia of speech (AOS) (Gorno-Tempini et al., 2011, Grossman et al., 1996, Ogar et al., 2007). Imaging studies in nfvPPA patients have shown left-lateralized atrophy mostly in the posterior frontal lobe, including Broca's area and premotor cortex, as well as in the anterior insula (Gorno-Tempini et al., 2004, Josephs et al., 2006, Nestor et al., 2003, Rogalski et al., 2011, Rohrer et al., 2009).

BvFTD is characterized by prominent progressive changes in personality and social–emotional function. Typical symptoms include disinhibition, altered eating behavior, loss of empathy, apathy, compulsivity and emotional dysregulation. Aberrant eating behavior is one of the most common and distinctive symptoms of bvFTD (Bozeat, Gregory, Ralph, & Hodges, 2000). It occurs in over 80% of bvFTD patients over the course of the disease (Piguet, Hornberger, Shelley, Kipps, & Hodges, 2009) and is characterized by gluttonous and indiscriminant food consumption (Shinagawa et al., 2009, Snowden et al., 2001). BvFTD neuroimaging studies have shown areas of atrophy in the ventromedial and posterior orbital frontal cortex, as well as the anterior insula and anterior cingulate cortex, striatum, and amygdala bilaterally but often more prominently on the right (Boccardi et al., 2005, Franceschi et al., 2005, Ibach et al., 2004, Rosen et al., 2002, Schroeter et al., 2007).

Despite the broad clinical and anatomical differences between bvFTD and nfvPPA, both disorders share regions of focal neurodegeneration in the insulae. Recent evidence highlights differential roles of anterior insular sub-regions in sensory-motor, cognitive, control and attentional, and behavioral functions (Deen et al., 2011, Kurth et al., 2010, Mutschler et al., 2009, Nelson et al., 2010, Touroutoglou et al., 2012). We predicted that the left superior precentral region of the dorsal anterior insula (SPGI), previously implicated in motor speech planning (Dronkers, 1996), would be most involved in nfvPPA, whereas the ventral anterior insula, previously linked to social–emotional and autonomic functions (Wooley et al., 2007), would be more atrophied in bvFTD. To test these hypotheses, we compared the patterns of MRI-based regional gray matter (GM) atrophy between early-stage nfvPPA and bvFTD. In particular, we investigated distinct subregions of the insulae to isolate specific foci of focal GM atrophy associated with each clinical presentation. Correlation analyses between these specific sub-regional volumes and relevant clinical scores were performed.

Section snippets

Subjects

We searched the University of California San Francisco (UCSF) Memory and Aging Center (MAC) database for patients who met the following inclusion criteria: a research diagnosis of bvFTD or nfvPPA, a high-resolution magnetic resonance imaging (MRI), and a Clinical Dementia Rating (CDR) score ≤ 1 (Morris, 1993) within 6 months of first diagnosis. Detailed clinical history, neurological examination, and neuropsychological screening were conducted as previously described (Rosen et al., 2002).

Group demographic and neuropsychological features

Consistent with our inclusion criteria, patient groups were similar in age, education, CDR score, box-score, and MMSE (Table 1). Neuropsychological assessment also revealed comparable general cognitive profiles between the two patient groups. Consistent with clinical diagnosis, bvFTD patients were significantly worse in their behavioral scores from the Neuropsychiatric Inventory (NPI) such as aberrant eating, disinhibition, apathy, euphoria, and aberrant motor scores. NfvPPA patients were

Discussion

This study evaluated patterns of brain atrophy in patients with early stage nfvPPA and bvFTD, with a particular focus on the insula. Consistent with their clinical profiles, nfvPPA and bvFTD showed distinctive atrophy patterns affecting the left and right anterior insula regions respectively. Within the insulae, nfvPPA patients showed greater atrophy in the left SPGI, while bvFTD patients showed greater atrophy in bilateral ventral anterior insular atrophy. Furthermore, volume changes in these

Conclusion

In summary, this study showed that patients with early nfvPPA and bvFTD present differential patterns of atrophy in the speech production and salience networks in accordance to their typical language and behavioral presentations. We suggested, for the first time, differential involvement of dorsal precentral and ventral anterior insula sub-regions in nfvPPA and bvFTD respectively. The findings highlight these insular sub-regions as possible early imaging biomarkers of disease in these syndromes

Acknowledgments

The study was supported by grants from the National Institutes of Health (NINDS R01 NS050915, NIA P50 AG03006, NIA P50 AG023501, NIA P01 AG019724); State of California (DHS04-35516); Alzheimer's Disease Research Centre of California (03–75271 DHS/ADP/ARCC); Larry L. Hillblom Foundation; John Douglas French Alzheimer's Foundation; Koret Family Foundation; Consortium for Frontotemporal Dementia Research; and McBean Family Foundation and a Career Scientist Award (NFD) from the US Department of

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