Behavioural neurologyTwo insular regions are differentially involved in behavioral variant FTD and nonfluent/agrammatic variant PPA
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
References (56)
- et al.
The contribution of the insula to motor aspects of speech production: a review and a hypothesis
Brain and Language
(2004) A fast diffeomorphic image registration algorithm
NeuroImage
(2007)- et al.
Frontotemporal dementia as a neural system disease
Neurobiology of Aging
(2005) - et al.
A core system for the implementation of task sets
Neuron
(2006) - et al.
Contrasting metabolic impairment in frontotemporal degeneration and early onset Alzheimer's disease
NeuroImage
(2004) - et al.
Functional organization of the human anterior insular cortex
Neuroscience Letters
(2009) - et al.
Group analyses of connectivity-based cortical parcellation using repeated k-means clustering
NeuroImage
(2009) - et al.
Towards a nosology for frontotemporal lobar degenerations-a meta-analysis involving 267 subjects
NeuroImage
(2007) - et al.
Neurodegenerative diseases target large-scale human brain networks
Neuron
(2009 Apr 16) - et al.
A common role of insula in feelings, empathy and uncertainty
Trends in Cognitive Sciences
(2009)
Fast and robust parameter estimation for statistical partial volume models in brain MRI
NeuroImage
Dissociable large-scale networks anchored in the right anterior insula subserve affective experience and attention
NeuroImage
Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer's disease?
Journal of Neurology, Neurosurgery & Psychiatry
Disgust sensitivity predicts the insula and pallidal response to pictures of disgusting foods
European Journal of Neuroscience
How do you feel-now? the anterior insula and human awareness
Nature Reviews Neuroscience
Neural mechanisms of autonomic, affective, and cognitive integration
The Journal of Comparative Neurology
The neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia
Neurology
Three systems of insular functional connectivity identified with cluster analysis
Cerebral Cortex
Distinct brain networks for adaptive and stable task control in humans
Proceedings of the National Academy of Sciences of the United States of America
A new brain region for coordinating speech articulation
Nature
Die Cytoarchitektonik der Hirnrinde des Erwachsenen Menschen
Glucose metabolism and serotonin receptors in the frontotemporal lobe degeneration
Annals of Neurology
Boston diagnostic aphasia examination (BDAE)
Cognition and anatomy in three variants of primary progressive aphasia
Annals of Neurology
Classification of primary progressive aphasia and its variants
Neurology
Progressive nonfluent aphasia: language, cognitive, and PET measures contrasted with probable Alzheimer's disease
Journal of Cognitive Neuroscience
Re-examining the brain regions crucial for orchestrating speech articulation
Brain
Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech
Brain
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