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Cited by 151Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

Distinct subtypes of behavioral variant frontotemporal dementia based on patterns of network degeneration

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Ranasinghe, Kamalini G., Rankin, Katherine P., Pressman, Peter S., Perry, David C., Lobach, Iryna V., Seeley, William W., Coppola, Giovanni, Karydas, Anna M. +26 more·2016·JAMA Neurology
DOI 10.1001/jamaneurol.2016.2016PMC PMC5024785
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Abstract

IMPORTANCE: Clearer delineation of the phenotypic heterogeneity within behavioral variant frontotemporal dementia (bvFTD) will help uncover underlying biological mechanisms and improve clinicians' ability to predict disease course and to design targeted management strategies. OBJECTIVE: To identify subtypes of bvFTD syndrome based on distinctive patterns of atrophy defined by selective vulnerability of specific functional networks targeted in bvFTD using statistical classification approaches. DESIGN, SETTING AND PARTICIPANTS: In this retrospective observational study, 90 patients meeting the Frontotemporal Dementia Consortium consensus criteria for bvFTD underwent evaluation at the Memory and Aging Center of the Department of Neurology at University of California, San Francisco. Patients underwent a multidisciplinary clinical evaluation, including clinical demographics, genetic testing, symptom evaluation, neurologic examination, neuropsychological bedside testing, and socioemotional assessments. All patients underwent structural magnetic resonance imaging at their earliest evaluation at the memory clinic. From each patient's structural imaging scans, the mean volumes of 18 regions of interest (ROI) constituting the functional networks specifically vulnerable in bvFTD, including the salience network (SN), with key nodes in the frontoinsula and pregenual anterior cingulate, and the semantic appraisal network (SAN), anchored in the anterior temporal lobe and subgenual cingulate, were estimated. Principal component and cluster analyses of ROI volumes were used to identify patient clusters with anatomically distinct atrophy patterns. Data were collected from from June 19, 2002, to January 13, 2015. MAIN OUTCOMES AND MEASURES: Evaluation of brain morphology and other clinical features, including presenting symptoms, neurologic examination signs, neuropsychological performance, rate of dementia progression, and socioemotional function, in each patient cluster. RESULTS: Ninety patients (54 men [60%]; 36 women [40%]; mean [SD] age at evaluation, 55.1 [9.7] years) were included in the analysis. Four subgroups of patients with bvFTD with distinct anatomic patterns of network degeneration were identified, including 2 salience network-predominant subgroups (frontal/temporal [SN-FT] and frontal [SN-F]), a semantic appraisal network-predominant group (SAN), and a subcortical-predominant group. Subgroups demonstrated distinct patterns of cognitive, socioemotional, and motor symptoms, as well as genetic compositions and estimated rates of disease progression. CONCLUSIONS AND RELEVANCE: Divergent patterns of vulnerability in specific functional network components make an important contribution to the clinical heterogeneity of bvFTD. The data-driven anatomic classification identifies biologically meaningful anatomic phenotypes and provides a replicable approach to disambiguate the bvFTD syndrome.

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  • Individuals diagnosed clinically with bvFTD typically show significant gray matter volume loss of the frontal and temporal lobes, with early and most significant loss of volume in the insula and anterior cingulate cortex.

    “Individuals diagnosed clinically with bvFTD typically show significant gray matter volume loss of the frontal and temporal lobes, with early and most significant loss of volume in the insula and anterior cingulate cortex (Seeley et al., 2008; Mandelli et al., 2016; Ranasinghe et al., 2016).”

    From Differential diagnosis of frontotemporal dementia subtypes with explainable deep learning on structural MRI (2024) · cites this paper as Ranasinghe et al., 2016

    The Introduction identifies the frontoinsula and pregenual anterior cingulate as nodes of a network vulnerable in bvFTD. The Results (bvFTD subgroup analyses; page unavailable) report significant cortical atrophy in three subgroups, but only one showed both frontal and temporal gray matter loss. The paper does not establish that insular and anterior cingulate volume loss occurs earliest or is the most significant. (LLM, conf=0.86)

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Authors
Ranasinghe, K. G., Rankin, K. P., Pressman, P. S., Perry, D. C., Lobach, I. V., Seeley, W. W., Coppola, G., Karydas, A. M., Grinberg, L. T., Shany-Ur, T., Lee, S. E., Rabinovici, G. D., Rosen, H. J., Gorno-Tempini, M. L., Boxer, A. L., Miller, Z. A., Chiong, W., DeMay, M., Kramer, J. H., Possin, K. L., Sturm, V. E., Bettcher, B. M., Neylan, M., Zackey, D. D., Nguyen, L. A., Ketelle, R., Block, N., Wu, T. Q., Dallich, A., Russek, N., Caplan, A., Geschwind, D. H., Vossel, K. A., & Miller, B. L.
Affiliations
  • Gladstone Institutes (US)
  • Memory and Aging Center, Department of Neurology, University of California, San Francisco
Corresponding author
Rankin, Katherine P.
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2016-09-01
Volume
73
Issue
9
Pages
1078
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2016.2016
PMC
PMC5024785
OpenAlex
W2494252203
Cited by
151
References
8
Citations by year
2026: 9 · 2025: 13 · 2024: 19 · 2023: 14 · 2022: 15 · 2021: 24 · 2020: 13 · 2019: 16 · 2018: 14 · 2017: 13 · 2016: 1
FWCI
13.03
Type
journal article
Language
en
Open access
Locations
  • JAMA Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Alzheimer's Association (2015-A-034-FEL, PCTRB-13-288476)
  • Larry L. Hillblom Foundation (2007/2I, 2015‐A‐034‐FEL, 2013-A-029-SUP)
  • National Institutes of Health
  • National Institute on Aging (K23AG021606, K23AG038357, L30 AG038306, R01AG029577, K23AG037566, K23AG042492, K23AG040127, K23AG048291, RF1AG029577, K23AG039414, R01AG032306, K23AG045289, K24AG045333, R01AG038791, U01AG052943, P01AG019724, P50AG023501)
  • National Institute on Deafness and Other Communication Disorders (K24DC015544)
  • National Institute of Neurological Disorders and Stroke (U54NS092089, R01NS050915)
  • National Center for Research Resources (L30 RR022879)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
behavioral variant frontotemporal dementia, salience network, brain atrophy patterns, subcortical atrophy, disease progression, genetic subtypes, prefrontal cortex, anterior temporal lobe, subgenual cingulate
MeSH terms
C9orf72 Protein, Aged, Mental Disorders, Brain, Cross-Sectional Studies, Female, Genetic Testing, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Mental Status Schedule, Middle Aged, Mutation, Neuropsychological Tests, Proteins, Retrospective Studies, Severity of Illness Index, tau Proteins, Frontotemporal Dementia

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