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Original Investigation |

Distinct Subtypes of Behavioral Variant Frontotemporal Dementia Based on Patterns of Network Degeneration

Kamalini G. Ranasinghe, MBBS, PhD1; Katherine P. Rankin, PhD1; Peter S. Pressman, MD1; David C. Perry, MD1; Iryna V. Lobach, PhD1,2; William W. Seeley, MD1,3; Giovanni Coppola, MD4; Anna M. Karydas, BA1; Lea T. Grinberg, MD, PhD1,3; Tal Shany-Ur, PhD1; Suzee E. Lee, MD1; Gil D. Rabinovici, MD1; Howard J. Rosen, MD1; Maria Luisa Gorno-Tempini, MD, PhD1; Adam L. Boxer, MD, PhD1; Zachary A. Miller, MD1; Winston Chiong, MD, PhD1; Mary DeMay, MD1; Joel H. Kramer, PsyD1; Katherine L. Possin, PhD1; Virginia E. Sturm, PhD1; Brianne M. Bettcher, PhD1,5; Michael Neylan, BA1; Diana D. Zackey, BA1; Lauren A. Nguyen, MA1; Robin Ketelle, MS, RN1; Nikolas Block, BA1; Teresa Q. Wu, BA1; Alison Dallich, BS1; Natanya Russek, BS1; Alyssa Caplan, BA1; Daniel H. Geschwind, MD, PhD6; Keith A. Vossel, MD, MSc1,7; Bruce L. Miller, MD1
[+] Author Affiliations
1Memory and Aging Center, Department of Neurology, University of California, San Francisco
2Department of Epidemiology and Biostatistics, University of California, San Francisco
3Department of Pathology, University of California, San Francisco
4Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles
5Departments of Neurosurgery and Neurology, University of Colorado Anschutz School of Medicine, Aurora
6Center for Autism Research and Treatment, University of California, Los Angeles
7Gladstone Institute of Neurological Disease, San Francisco, California
JAMA Neurol. 2016;73(9):1078-1088. doi:10.1001/jamaneurol.2016.2016.
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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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Figure 1.
Frequency of Diagnostic Criteria and Major Symptom Domains in Behavioral Variant Frontotemporal Dementia (bvFTD)

Diagnostic criteria used the International Behavioral Variant FTD Criteria Consortium revised guidelines. A, Frequency of core diagnostic features of patients with bvFTD. B, Percentage of patients with the initial symptoms in the behavior, executive, memory, language, and motor domains. C, Rates of National Alzheimer Coordinating Center behavioral symptom checklist categories in patients with bvFTD during the first 12 months of presenting to the memory clinic (n = 81). Only the top 6 symptoms are shown in descending order from top to bottom. D, The rates of symptoms in each of the main domains in patients with bvFTD categorized according to their disease severity (measured by frontotemporal lobar degeneration–modified Clinical Dementia Rating Sum of Boxes [FTLD-modified CDR-SOB] score).

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Figure 2.
Anatomic Subtypes of Behavioral Variant Frontotemporal Dementia (bvFTD)

Patients with bvFTD are clustered into 4 distinct subgroups based on the degree of atrophy in 18 regions of interest (ROIs) defining the functional salience network (SN) and semantic appraisal network (SAN). The SN-affected groups include a frontal/temporal-predominant (SN-FT) subgroup and a frontal-predominant subgroup (SN-F). There was also a SAN-predominant subgroup and a subcortical-predominant subgroup. A, In the top panel, each patient is colored according to his or her cluster assignment and plotted onto the first 2 dimensions of a principal component analysis based on the same 18 ROIs. In the bottom panels, the gray scale indicates the normalized volume of the sum of each patient’s ROIs representing the SN and SAN networks, where darker colors indicate a greater degree of volume loss. B, Voxel-based morphometry–derived atrophy maps of each bvFTD subgroup. The t value maps show the atrophy patterns compared with age-matched normal controls (n = 44) and are superimposed onto a whole-brain template derived from older (mean [SD] age, 67.3 [9.2] years) normal controls. Effects are corrected for age, sex, and total intracranial volume of each individual and for family-wise error at the whole brain level at P < .05. MNI (Montreal Neurological Institute) coordinates are shown. C, Percentage of mutation carriers for C9orf72, MAPT, or GRN mutations in each subgroup. D, Percentage of patients found to have specific classes of neuropathologic features associated with each bvFTD subgroup among the subset of patients with autopsy diagnosis. Patients who were diagnosed as having tau (other) pathologic findings included 2 in the SN-FT subgroup with frontotemporal lobar degeneration (FTLD)-tau with the MAPT mutation, 1 in the SAN subgroup with frontotemporal dementia with parkinsonism-17 (FTDP17), and 1 in the subcortical group with argyrophilic grain disease. CBD indicates corticobasal degeneration; TDP, transactive response DNA-binding protein 43.

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Figure 3.
Rate of Disease Progression in Behavioral Variant Frontotemporal Dementia (bvFTD) Subgroups

Patients in the subcortical subgroup showed a slower progression of dementia compared with other bvFTD subgroups, as measured by the frontotemporal lobar degeneration–modified Clinical Dementia Rating Sum of Boxes (FTLD-modified CDR-SOB). The x-axis plots the difference of time between the first and the last evaluation, and the y-axis shows the difference in FTLD-modified CDR-SOB scores between the 2 evaluations. The analysis includes a subset of patients with bvFTD who have more than 1 evaluation (n = 59). The open green circle indicates a single patient with bvFTD whom we have identified as an outlier and who was not included in the regression equation (eMethods in the Supplement); analysis of variance with contrast analysis showed a slower rate of progression in the subcortical subgroup compared with others (F = 3.5; P = .07). The salience network–predominant frontal/temporal (SN-FT) subgroup included 16 patients; the salience network–predominant frontal (SN-F) subgroup, 14 patients; the semantic appraisal network–predominant (SAN) subgroup, 7 patients; and the subcortical-predominant subgroup, 21 patients. Regression equations for each subgroup were y = 1.7x + 2.04, y = 1.4x + 4.17, y = 2.3x − 0.52, and y = 0.2x + 3.28, respectively.

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Figure 4.
Diagnostic Criteria, Presenting Symptoms, and Socioemotional Dysfunction in Behavioral Variant Frontotemporal Dementia (bvFTD) Subgroups

Diagnostic criteria used the International Behavioral Variant FTD Criteria Consortium revised guidelines. A, Frequency of core diagnostic features in each bvFTD subgroup. B, Percentage of patients in each bvFTD subgroup with the initial symptoms in behavior, executive, memory, language, and motor domains. C, Rates of National Alzheimer Coordinating Center behavioral symptom checklist categories in each bvFTD subgroup during the first 12 months of presenting to the memory clinic. Only the top 6 symptoms are shown in descending order from top to bottom. D, Rates of specific socioemotional impairments observed in each bvFTD subgroup. Socioemotional function was considered impaired at a z score less than 1.35 based on published normative samples of age-matched healthy controls. Complex social cognition, emotion naming, and sarcasm detection (paralinguistic, ie, voice prosody and facial expression) abilities were measured with The Awareness of Social Inference Test (complex social cognition range, 0-64; emotion naming range, 0-14; and sarcasm detection range, 0-20. Higher scores indicate better performance in each measure). Cognitive perspective taking was assessed with the UCSF Cognitive Theory of Mind test (range, 0-16, with higher scores indicating better performance). Interpersonal assertiveness and warmth were measured with the Dominance and Warmth subscales of the Interpersonal Adjective Scales (range, 0-64, with higher scores indicating better performance). Empathy was measured with the Empathic Concern and Perspective Taking subscales of Interpersonal Reactivity Index, each ranging from 7 to 35, with higher scores indicating better performance. SAN indicates semantic appraisal network–predominant subgroup; SN-FT, salience network–predominant frontal/temporal subgroup; and SN-F, salience network–predominant frontal subgroup.

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