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Regional prefrontal cortical atrophy predicts specific cognitive-behavioral symptoms in ALS-FTD

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Abstract

Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD) may present typical behavioral variant FTD symptoms. This study aims to determine whether profile and severity of cognitive-behavioral symptoms in ALS/ALS-FTD are predicted by regional cortical atrophy. The hypothesis is that executive dysfunction can be predicted by dorsolateral prefrontal cortical (dlPFC) atrophy, apathy by dorsomedial PFC (dmPFC) and anterior cingulate cortical (ACC) atrophy, disinhibition by orbitofrontal cortical (OFC) atrophy. 3.0 Tesla MRI scans were acquired from 22 people with ALS or ALS-FTD. Quantitative cortical thickness analysis was performed with FreeSurfer. A priori-defined regions of interest (ROI) were used to measure cortical thickness in each participant and calculate magnitude of atrophy in comparison to 115 healthy controls. Spearman correlations were used to evaluate associations between frontal ROI cortical thickness and cognitive-behavioral symptoms, measured by Neuropsychiatric Inventory Questionnaire (NPI-Q) and Clinical Dementia Rating (CDR) scale. ALS-FTD participants exhibited variable degrees of apathy (NPI-Q/apathy: 1.6 ± 1.2), disinhibition (NPI-Q/disinhibition: 1.2 ± 1.2), executive dysfunction (CDR/judgment-problem solving: 1.7 ± 0.8). Within the ALS-FTD group, executive dysfunction correlated with dlPFC atrophy (ρ:-0.65;p < 0.05); similar trends were seen for apathy with ACC (ρ:-0.53;p < 0.10) and dmPFC (ρ:-0.47;p < 0.10) atrophy, for disinhibition with OFC atrophy (ρ:-0.51;p < 0.10). Compared to people with ALS, those with ALS-FTD showed more diffuse atrophy involving precentral gyrus, prefrontal, temporal regions. Profile and severity of cognitive-behavioral symptoms in ALS-FTD are predicted by regional prefrontal atrophy. These findings are consistent with established brain-behavior models and support the role of quantitative MRI in diagnosis, management, counseling, monitoring and prognostication for a neurodegenerative disorder with diverse phenotypes.

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Data availability

The datasets generated during and/or analyzed during the current study may be available from the corresponding author on reasonable request.

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Acknowledgments

We express special appreciation to the participants in this study and their families for their valuable contributions, without which this research would not have been possible. We thank the staff at the Martinos Center for Biomedical Imaging, particularly Mary Foley and Larry White, for their technical expertise, and Jeanette Gunther and the staff of the MGH ADRC and the MGH Neurological Clinical Research Institute for their expertise in coordinating and evaluating participants in the Longitudinal Cohort and with ALS measures, respectively. We are also grateful to Elena Ratti’s Master’s thesis committee advisors, Dr. Darin Dougherty and Dr. Catherine Lomen-Hoerth, for their precious advice and guidance for the success of this study.

Funding

This study was funded by: MGH Neurology Clinical Research Institute, Massachusetts ADRC and Harvard NeuroDiscovery Center’s 2013 Pilot Award Program; National Institute of Neurological Disorders and Stroke (NINDS): R25 NS065743; R21 NS079905; R01 AG030311; P01 AG005134; and the Dr. Anne B. Young Neuroscience Translational Medicine Fellowship (Massachusetts General Hospital Neurology and Biogen).

The sponsors did not have any involvement in the study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the article for publication.

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Author notes

  1. Elena Ratti

    Present address: Biogen, 300 Binney Street, Cambridge, MA, 02142, USA

  2. Kimiko Domoto-Reilly & Christina Caso

    Present address: Department of Neurology, University of Washington Medical Center, 1959 NE Pacific Street, Seattle, WA, 98195, USA

Authors and Affiliations

  1. Neurological Clinical Research Institute (NCRI), Massachusetts General Hospital, 165 Cambridge Street, Suite 600, Boston, MA, 02114, USA

    Elena Ratti, Alyssa Murphy & Merit E. Cudkowicz

  2. Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA

    Elena Ratti, Kimiko Domoto-Reilly, Christina Caso, Michael Brickhouse, Daisy Hochberg & Bradford C. Dickerson

  3. Amyotrophic Lateral Sclerosis Multidisciplinary Clinic, Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA

    Elena Ratti, Alyssa Murphy & Merit E. Cudkowicz

  4. Massachusetts Alzheimer’s Disease Research Center (ADRC), 149 13th Street, Charlestown, MA, 02129, USA

    Elena Ratti, Kimiko Domoto-Reilly & Bradford C. Dickerson

  5. Athinoula A. Martinos Center for Biomedical Imaging, 149 13th Street, Charlestown, MA, 02129, USA

    Elena Ratti, Kimiko Domoto-Reilly & Bradford C. Dickerson

  6. Speech and Language Pathology, Massachusetts General Hospital, 275 Cambridge Street, Boston, MA, 02114, USA

    Daisy Hochberg

  7. Department of Psychiatry, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA

    Nikos Makris

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Contributions

Elena Ratti: study concept and design, data acquisition, data analysis, manuscript preparation, critical revision of the manuscript for important intellectual content.

Kimiko Domoto-Reilly: data acquisition, critical revision of the manuscript for important intellectual content.

Christina Caso: data acquisition and data analysis.

Alyssa Murphy: data acquisition.

Michael Brickhouse: data acquisition and data analysis.

Daisy Hochberg: data acquisition.

Nikos Makris: study concept and design, data analysis, critical revision of the manuscript for important intellectual content.

Merit E. Cudkowicz: study concept and design, critical revision of the manuscript for important intellectual content.

Bradford C. Dickerson: study concept and design, data acquisition, data analysis, manuscript preparation, critical revision of the manuscript for important intellectual content.

Corresponding author

Correspondence to Elena Ratti.

Ethics declarations

Ethical approval

The Partners Human Research Committee at Massachusetts General Hospital has approved the involvement of human subjects in this study.

Consent to participate

All participants provided written informed consent in accordance with the Partners Human Research Committee at Massachusetts General Hospital guidelines.

Consent for publication

All participants provided written informed consent that included potential of sharing anonymized information collected during this study with the general scientific community.

Competing interests

Elena Ratti received fellowship grants from the National Institute of Neurological Disorders and Stroke (NINDS) with grant number R25NS065743, title: Neuroscience resident research program, and the Dr. Anne B. Young Neuroscience Translational Medicine Fellowship (Massachusetts General Hospital Neurology and Biogen). She had research grants from the Harvard NeuroDiscovery Center and the Amyotrophic Lateral Sclerosis Association (ALSA). She is now a Biogen employee.

Kimiko Domoto-Reilly receives research funding from NIA grants P30 AG066509, U19 AG063911, and R01 AG066957, and also from Lawson Health Research Institute and Alzheimer’s Therapeutic Research Institute. She has received speaker fees, unrelated to work presented in this manuscript, from Med Learning Group and MedBridge.

Christina Caso reports no disclosures.

Alyssa Murphy reports no disclosures.

Michael Brickhouse reports no disclosures.

Daisy Hochberg reports no disclosures.

Nikos Makris received funding from grants R21NS079905, R21NS077059, R21EB016449, R01AG042512.

Merit E. Cudkowicz has received consultation fees, unrelated to work presented in this manuscript, from Biogen, Genentech, Cytokinetics, Biohaven, Voyager and Astra Zeneca.

Bradford C. Dickerson has received consultation fees, unrelated to work presented in this manuscript, from Merck, Forum, Ionis, Med Learning Group, Catamount, and Haymarket Medical Media. He also receives royalties from Oxford University Press.

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Ratti, E., Domoto-Reilly, K., Caso, C. et al. Regional prefrontal cortical atrophy predicts specific cognitive-behavioral symptoms in ALS-FTD. Brain Imaging and Behavior 15, 2540–2551 (2021). https://doi.org/10.1007/s11682-021-00456-1

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