Shape analysis of the neostriatum in frontotemporal lobar degeneration, Alzheimer's disease, and controls

Abstract

Background and purpose: Frontostriatal circuit mediated cognitive dysfunction has been implicated in frontotemporal lobar degeneration (FTLD), but not Alzheimer's disease, or healthy aging. We measured the neostriatum (caudate nucleus and putamen) volume in FTLD (n = 34), in comparison with controls (n = 27) and Alzheimer's disease (AD, n = 19) subjects. Methods: Diagnoses were based on international consensus criteria. Manual bilateral segmentation of the caudate nucleus and putamen was conducted blind to diagnosis by a single analyst, on MRI scans using a standardized protocol. Intra-cranial volume was calculated via a stereological point counting technique and was used for scaling the shape analysis. The manual segmentation binaries were analyzed using UNC Shape Analysis tools (University of North Carolina) to perform comparisons among FTLD, AD, and controls for global shape, local p-value significance maps, and mean magnitude of shape displacement. Results: Shape analysis revealed that there was significant shape difference between FTLD, AD, and controls, consistent with the predicted frontostriatal dysfunction and of significant magnitude, as measured by displacement maps. There was a lateralized difference in shape for the left caudate for FTLD compared to AD; non-specific global atrophy in AD compared to controls; while FTLD showed a more specific pattern in regions relaying fronto- and corticostriatal circuits. Conclusions: Shape analysis shows regional specificity of atrophy, manifest as shape deflation, with implications for frontostriatal and corticostriatal motoric circuits, in FTLD, AD, and controls.

Introduction

The cognitive and behavioral abnormalities identified in FTLD may be conceptualized in terms of dysfunction in frontostriatal circuits (Hodges and Patterson, 2007). Frontostriatal circuits or loops include a discrete prefrontal region, which sends efferent pathways through the neostriatum (caudate nucleus, putamen) or nucleus accumbens, via the globus pallidus, onto the thalamus, and thence back to that specific prefrontal cortex (Alexander et al., 1986). These loops include motor loops originating in the frontal eye fields and supplementary motor cortex, as well as “cognitive loops” arising from dorsolateral prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex (Alexander et al., 1986). Circuit dysfunction may result in characteristic cognitive and behavioral syndromes (Cummings, 1993).

Cognitive/behavioral dysfunction mediated via frontostriatal circuits in FTLD may be reflected in structural change in components of that circuitry. A meta-analysis of both structural and functional imaging of FTLD and controls demonstrated the existence of characteristic patterns of activation and atrophy for each of the subtypes of FTLD in prefrontal cortex, temporal lobe, amygdala, and neostriatum (Schroeter et al., 2007). While FTLD has traditionally been considered to result from disease of frontal or temporal cortex, these findings indicate that the neostriatum may be involved. The neostriatum serves as an entry point for afferent information from the periphery, as well as for afferents and efferents for functionally segregated regions of the cortex (Alexander et al., 1986, Haber et al., 2000, Haber, 2003). Cortical atrophy may lead to loss of inputs to the neostriatum and neuroplastic reduction in the volume of the neostriatum. Severe atrophy of the caudate and putamen was noted long ago in FTLD (von Braunmühl and Picksche, 1930, von Bagh, 1946, Lüers and Spatz, 1957) but, until recently, had not been demonstrated using quantitative data or methods.

Our recent volumetric studies of FTLD showed reductions in the volume of the caudate by up to 25% of control volume (FTD subtype) and by up to 13% of control volume in the putamen (PNFA subtype), in contrast to minimal volumetric change in AD compared to controls (Looi et al., 2008b, Looi et al., 2009b). We also demonstrated that there was a gradation in severity of atrophy consistent with the severity of theoretical frontostriatal dysfunction, with greatest atrophy in the FTD subtype of FTLD for the caudate and more uniform atrophy across all FTLD subtypes in the putamen.

Such volumetric studies do not resolve regional morphologic change in the neostriatum. Thompson (1945) observed that morphology may be determined by growth, that the form of living organisms accords with their functions, and developed mathematical methods for measuring organic morphology. We investigated whether FTLD is associated with disturbed morphology of neostriatal structures. Neostriatal components are ideal candidate structures for morphological or shape analysis due to the highly specific nature of their regional interconnections.

The caudate and putamen are each divided into functional subregions based on afferents received from the frontal cortex and substantia nigra (Haber et al., 2000, Haber, 2003). The caudate head and body receives connections on its lateral aspect from the dorsolateral prefrontal cortex, inferior orbitofrontal cortex, and posterior parietal cortex, whereas the tail receives input from the frontal eye fields. On its medial aspect, the caudate is connected to the anterior cingulate cortex (Alexander et al., 1986, Haber et al., 2000, Heimer and Van Hoesen, 2006, Utter and Basso, 2008). The putamen receives connections on its medial aspect from the motor cortex and somatosensory cortex. The lateral putamen receives connections from the supplementary motor area. Haber et al. (2003) and Haber (2000) have described connections from the dorsolateral prefrontal cortex to the ventral aspect of the putamen. In addition, there are fibers traversing the internal capsule linking the caudate and putamen above their mutual origin in the nucleus accumbens (Alexander et al., 1986, Heimer and Van Hoesen, 2006, Utter and Basso, 2008, Draganski et al., 2008). Regional changes in the shape of the caudate and putamen may be associated with dysfunction of specific circuits with resultant clinical consequences.

Spherical harmonic shape analysis of the caudate and putamen has the potential to resolve localized areas of morphological change (Gerig and Styner, 2001, Styner et al., 2004, Styner et al., 2005, Styner et al., 2006). Levitt et al., 2004, Levitt et al., 2009), Hwang et al., 2006, Choi et al., 2007, and Mamah et al., (2008) have previously applied shape analysis to the striatum in schizotypal personality disorder, bipolar disorder, obsessive-compulsive disorder, and siblings of persons with schizophrenia, respectively. Levitt et al. (2009) found an association between shape deflation and verbal learning capacity in females with SPD, implicating frontostriatal connections to the ventromedial prefrontal cortex. Qiu et al. (2009) applied high-dimensional shape analysis to patients with mild cognitive impairment, AD, and controls, while another group has studied morphologic change with aging (Koikkalainen et al., 2007).

Thus, based on our previous volumetric studies in neuropsychiatric disease and FTLD (Looi et al., 2008b, Looi et al., 2009a, Looi et al., 2009b, Looi et al., 2009c), and the shape change of the striatum shown in other disease, we hypothesized that the morphology of the caudate and putamen would differ between FTLD in comparison to Alzheimer's disease, in which frontostriatal dysfunction is not a major feature, and controls, that is:

• The group average shape of the caudate and putamen would differ between AD, controls, and the combined subtypes of FTLD;

• The group average shape of the caudate and putamen would differ between groups of AD, FTLD, and controls, based on the theoretical degree of frontostriatal circuit dysfunction (least shape change–Controls > AD > FTLD–greatest shape change);

• The group average shape differences will be distributed in regions corresponding to the putative degree of involvement of frontostriatal circuits in disease groups.