Behavioral changes in early ALS correlate with voxel-based morphometry and diffusion tensor imaging,☆☆

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Abstract

Background

Amyotrophic lateral sclerosis (ALS) is a multisystem disorder with impairment of frontotemporal functions such as cognition and behavior, but the behavioral changes associated with ALS are not well defined.

Methods

Twenty-one consecutive patients with sporadic ALS and 21 control subjects participated in the study. The Frontal System Behavior Scale (FrSBe) was used to assess behavioral change. Voxel-based morphometry (VBM) and voxel-based analysis of diffusion tensor images (DTI) were performed to explore the associations of brain degeneration with behavior. All patients were evaluated before the notification of ALS.

Results

FrSBe scores of ALS patients before notification were significantly increased compared to those of control subjects. Moreover, the FrSBe Apathy score of ALS patients significantly changed from pre- to post-illness (P < 0.001). The severity of apathy was significantly correlated with atrophy in the prefrontal cortex, especially in the orbitofrontal (P = 0.006) and dorsolateral prefrontal (P = 0.006) cortices in VBM, and in the right frontal gyrus (P < 0.001) in DTI.

Conclusions

ALS patients exhibited apathy during the early course of the illness, the severity of which was significantly associated with frontal lobe involvement. These findings support the view that a continuum exits between ALS and frontotemporal dementia.

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor involvement in limb, bulbar, and respiratory functions [1] and also shows symptoms involving non-motor systems [2], such as frontotemporal dysfunction (FTD) including cognitive decline [3] and behavioral impairment including personality change, apathy, disinhibition, and irritability. Moreover, there is evidence linking FTD and motor neuron disease [4], [5], [6], [7], [8].

The frontal symptoms such as apathy and disinhibition not only affect the patients' care, but also key clinical decisions, such as non-invasive positive pressure ventilation, enteral nutrition, intravenous hyperalimentation, and artificial ventilation [9]. Behavioral changes have been documented in ALS patients [10], although that study assessed the symptoms in relatively advanced stages of ALS. It is important to know whether these behavioral changes are also present during the early course of the illness, as the rapid progress of ALS impairments forces patients and their families to make key decisions during the early stage. Furthermore, behavioral symptoms that occur as early as the beginning of motor symptoms provide evidence that neuroanatomical systems related to behavioral changes are involved simultaneously with motor systems.

Reports have also demonstrated the importance of frontosubcortical circuits in determining behavior [11], [12]. However, an understanding of the neuroanatomical changes related to behavioral impairments in ALS patients is lacking. In this study, we evaluated the neurobehavioral symptoms of ALS patients and examined their neuroanatomical correlates of behavioral symptoms using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI).

Section snippets

Subjects

Patients participating in the study were admitted for diagnosis to the Nagoya University Hospital from May 2009 to June 2010. We enrolled 39 consecutively patients who were diagnosed as either laboratory supported, probable, or definite ALS by the EI Escorial criteria during their administration [13]. From these we selected early-stage ALS patients. The definition of early stage is difficult in ALS. Even in short duration patients, the dependent state is often associated with advanced

Results

Demographics and ALS-related variables are summarized in Table 1. The MMSE and FAB scores of ALS patients were significantly lower than those of controls (p < 0.001). The FrSBe post-illness scores were higher than the pre-illness scores, irrespective of the patients' scores for the ALSFRS-R, FVC, MMSE, and FAB. In particular, there was a significant difference between the pre- and post-illness apathy subscale FrSBe scores (Table 2), but no significant differences in either disinhibition or

Discussion

Our results demonstrated that even early ALS patients show significant increases in their FrSBe score. In particular, the apathy score showed a significant change from the pre to the post-illness stage. The apathy score was mildly but significantly changed. The score was correlated with reduced gray matter volume, decreased FA values, and increased MD values in the prefrontal lobe as demonstrated by VBM. Although the initial behavioral changes in ALS have not been fully investigated, these

Acknowledgements

This work was supported by Health and Labor Science Research Grants for Research on Measures for Intractable Diseases, and Comprehensive Research on Aging and Health by the Ministry of Health, Labor and Welfare, Japan.

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    The statistical analysis with our professional affiliation is academic.

    ☆☆

    Disclosure: All authors were supported by Health and Labor Science Research Grants for research on measures for intractable diseases and comprehensive research on Aging and Health of the Ministry of Health, Labor, and Welfare, Japan. We take full responsibility for the data, their analyses and interpretation, and the conduct of the research, and had full access to all of the data, and had the right to publish all data, separate and apart from the attitudes of the sponsor.

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