Distinct Subtypes of Behavioral Variant Frontotemporal Dementia Based on Patterns of Network Degeneration | Dementia and Cognitive Impairment | JAMA Neurology | JAMA Network
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1.
Neary  D, Snowden  JS, Gustafson  L,  et al.  Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria.  Neurology. 1998;51(6):1546-1554.PubMedGoogle ScholarCrossref
2.
Snowden  JS, Neary  D, Mann  DM.  Frontotemporal dementia.  Br J Psychiatry. 2002;180:140-143.PubMedGoogle ScholarCrossref
3.
Hodges  JR.  Frontotemporal dementia (Pick’s disease): clinical features and assessment.  Neurology. 2001;56(11)(suppl 4):S6-S10.PubMedGoogle ScholarCrossref
4.
Pievani  M, de Haan  W, Wu  T, Seeley  WW, Frisoni  GB.  Functional network disruption in the degenerative dementias.  Lancet Neurol. 2011;10(9):829-843.PubMedGoogle ScholarCrossref
5.
Seeley  WW, Crawford  RK, Zhou  J, Miller  BL, Greicius  MD.  Neurodegenerative diseases target large-scale human brain networks.  Neuron. 2009;62(1):42-52.PubMedGoogle ScholarCrossref
6.
Zhou  J, Gennatas  ED, Kramer  JH, Miller  BL, Seeley  WW.  Predicting regional neurodegeneration from the healthy brain functional connectome.  Neuron. 2012;73(6):1216-1227.PubMedGoogle ScholarCrossref
7.
Yeo  BT, Krienen  FM, Sepulcre  J,  et al.  The organization of the human cerebral cortex estimated by intrinsic functional connectivity.  J Neurophysiol. 2011;106(3):1125-1165.PubMedGoogle ScholarCrossref
8.
Seeley  WW, Zhou  J, Kim  EJ.  Frontotemporal dementia: what can the behavioral variant teach us about human brain organization?  Neuroscientist. 2012;18(4):373-385.PubMedGoogle ScholarCrossref
9.
Zhou  J, Seeley  WW.  Network dysfunction in Alzheimer’s disease and frontotemporal dementia: implications for psychiatry.  Biol Psychiatry. 2014;75(7):565-573.PubMedGoogle ScholarCrossref
10.
Guo  CC, Gorno-Tempini  ML, Gesierich  B,  et al.  Anterior temporal lobe degeneration produces widespread network-driven dysfunction.  Brain. 2013;136(pt 10):2979-2991.PubMedGoogle ScholarCrossref
11.
Rascovsky  K, Hodges  JR, Knopman  D,  et al.  Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.  Brain. 2011;134(pt 9):2456-2477.PubMedGoogle ScholarCrossref
12.
Morris  JC.  The Clinical Dementia Rating (CDR): current version and scoring rules.  Neurology. 1993;43(11):2412-2414.PubMedGoogle ScholarCrossref
13.
Borroni  B, Agosti  C, Premi  E,  et al.  The FTLD-modified Clinical Dementia Rating scale is a reliable tool for defining disease severity in frontotemporal lobar degeneration: evidence from a brain SPECT study.  Eur J Neurol. 2010;17(5):703-707.PubMedGoogle ScholarCrossref
14.
Folstein  MF, Folstein  SE, McHugh  PR.  “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12(3):189-198.PubMedGoogle ScholarCrossref
15.
McDonald  S, Bornhofen  C, Shum  D, Long  E, Saunders  C, Neulinger  K.  Reliability and validity of The Awareness of Social Inference Test (TASIT): a clinical test of social perception.  Disabil Rehabil. 2006;28(24):1529-1542.PubMedGoogle ScholarCrossref
16.
Shany-Ur  T, Poorzand  P, Grossman  SN,  et al.  Comprehension of insincere communication in neurodegenerative disease: lies, sarcasm, and theory of mind.  Cortex. 2012;48(10):1329-1341.PubMedGoogle ScholarCrossref
17.
Davis  MH.  Measuring individual differences in empathy: evidence for a multidimensional approach.  J Pers Soc Psychol. 1983;44(1):113-126.Google ScholarCrossref
18.
Rankin  KP, Gorno-Tempini  ML, Allison  SC,  et al.  Structural anatomy of empathy in neurodegenerative disease.  Brain. 2006;129(pt 11):2945-2956.PubMedGoogle ScholarCrossref
19.
Wiggins  JS, Trapnell  P, Phillips  N.  Psychometric and geometric characteristics of the Revised Interpersonal Adjective Scales (IAS-R).  Multivariate Behav Res. 1988;23(4):517-530.PubMedGoogle ScholarCrossref
20.
Interpersonal Adjective Scales (IAS) Scoring Program [computer program]. Version 1. Odessa, FL: Psychological Assessment Resources Inc; 1995.
21.
Rohrer  JD, Warren  JD.  Phenotypic signatures of genetic frontotemporal dementia.  Curr Opin Neurol. 2011;24(6):542-549.PubMedGoogle ScholarCrossref
22.
O’Bryant  SE, Waring  SC, Cullum  CM,  et al; Texas Alzheimer’s Research Consortium.  Staging dementia using Clinical Dementia Rating Scale Sum of Boxes scores: a Texas Alzheimer’s research consortium study.  Arch Neurol. 2008;65(8):1091-1095.PubMedGoogle ScholarCrossref
23.
Buckner  RL, Andrews-Hanna  JR, Schacter  DL.  The brain’s default network: anatomy, function, and relevance to disease.  Ann N Y Acad Sci. 2008;1124:1-38.PubMedGoogle ScholarCrossref
24.
Greicius  MD, Krasnow  B, Reiss  AL, Menon  V.  Functional connectivity in the resting brain: a network analysis of the default mode hypothesis.  Proc Natl Acad Sci U S A. 2003;100(1):253-258.PubMedGoogle ScholarCrossref
25.
Dosenbach  NU, Fair  DA, Miezin  FM,  et al.  Distinct brain networks for adaptive and stable task control in humans.  Proc Natl Acad Sci U S A. 2007;104(26):11073-11078.PubMedGoogle ScholarCrossref
26.
Dosenbach  NU, Fair  DA, Cohen  AL, Schlaggar  BL, Petersen  SE.  A dual-networks architecture of top-down control.  Trends Cogn Sci. 2008;12(3):99-105.PubMedGoogle ScholarCrossref
27.
Whitwell  JL, Przybelski  SA, Weigand  SD,  et al.  Distinct anatomical subtypes of the behavioural variant of frontotemporal dementia: a cluster analysis study.  Brain. 2009;132(pt 11):2932-2946.PubMedGoogle ScholarCrossref
28.
Whitwell  JL, Xu  J, Mandrekar  J,  et al.  Frontal asymmetry in behavioral variant frontotemporal dementia: clinicoimaging and pathogenetic correlates.  Neurobiol Aging. 2013;34(2):636-639.PubMedGoogle ScholarCrossref
29.
Whitwell  JL, Avula  R, Senjem  ML,  et al.  Gray and white matter water diffusion in the syndromic variants of frontotemporal dementia.  Neurology. 2010;74(16):1279-1287.PubMedGoogle ScholarCrossref
30.
Seeley  WW, Allman  JM, Carlin  DA,  et al.  Divergent social functioning in behavioral variant frontotemporal dementia and Alzheimer disease: reciprocal networks and neuronal evolution.  Alzheimer Dis Assoc Disord. 2007;21(4):S50-S57.PubMedGoogle ScholarCrossref
31.
Delis  DC, Kramer  JH, Kaplan  E, Ober  BA.  California Verbal Learning Test−Second Edition, Adult Version. San Antonio, TX: Psychological Corp; 2000.
32.
Possin  KL, Laluz  VR, Alcantar  OZ, Miller  BL, Kramer  JH.  Distinct neuroanatomical substrates and cognitive mechanisms of figure copy performance in Alzheimer’s disease and behavioral variant frontotemporal dementia.  Neuropsychologia. 2011;49(1):43-48.PubMedGoogle ScholarCrossref
33.
Kaplan  EF, Goodglass  H, Weintraub  S.  The Boston Naming Test. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.
34.
Mack  WJ, Freed  DM, Williams  BW, Henderson  VW.  Boston Naming Test: shortened versions for use in Alzheimer’s disease.  J Gerontol. 1992;47(3):154-158.PubMedGoogle ScholarCrossref
35.
Goodglass  H, Kaplan  E, Barresi  B.  Boston Diagnostic Aphasia Examination. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.
36.
Benton  AL, Hamsher  KD, Sivan  AB.  Multilingual Aphasia Examination. 3rd ed. San Antonio, TX: Psychological Corp; 1994.
37.
Spreen  O, Benton  AL.  Neurosensory Center Comprehensive Examination for Aphasia. Victoria, BC: Neuropsychology Laboratory, University of Victoria; 1977.
38.
Warrington  EK, James  M.  The Visual Object and Space Perception Battery. Bury St Edmunds, England: Thames Valley Test Co; 1991.
39.
Froming  K, Levy  M, Schaffer  S, Ekman  P.  The Comprehensive Affect Testing System. Sanford, FL: Psychology Software Inc; 2006.
40.
Delis  DC, Kaplan  E, Kramer  JH.  Delis-Kaplan Executive Function System. San Antonio, TX: Psychological Corp; 2001.
41.
Golden  CJ.  Stroop Color and Word Test: Revised Examiner’s Manual. Wood Dale, IL: Stoelting Co; 2002.
42.
Golden  CJ.  Stroop Color and Word Test: A Manual for Clinical and Experimental Uses. Chicago, IL: Stoelting Co; 1978.
43.
Josephs  KA, Whitwell  JL, Knopman  DS,  et al.  Two distinct subtypes of right temporal variant frontotemporal dementia.  Neurology. 2009;73(18):1443-1450.PubMedGoogle ScholarCrossref
44.
Rohrer  JD.  Behavioural variant frontotemporal dementia: defining genetic and pathological subtypes.  J Mol Neurosci. 2011;45(3):583-588.PubMedGoogle ScholarCrossref
45.
Kipps  CM, Hodges  JR, Hornberger  M.  Nonprogressive behavioural frontotemporal dementia: recent developments and clinical implications of the “bvFTD phenocopy syndrome.”  Curr Opin Neurol. 2010;23(6):628-632.PubMedGoogle ScholarCrossref
46.
Khan  BK, Yokoyama  JS, Takada  LT,  et al.  Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9orf72 hexanucleotide expansion.  J Neurol Neurosurg Psychiatry. 2012;83(4):358-364.PubMedGoogle ScholarCrossref
47.
Piguet  O, Hornberger  M, Mioshi  E, Hodges  JR.  Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management.  Lancet Neurol. 2011;10(2):162-172.PubMedGoogle ScholarCrossref
48.
Lee  SE, Khazenzon  AM, Trujillo  AJ,  et al.  Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion.  Brain. 2014;137(pt 11):3047-3060.PubMedGoogle ScholarCrossref
49.
O’Doherty  J, Kringelbach  ML, Rolls  ET, Hornak  J, Andrews  C.  Abstract reward and punishment representations in the human orbitofrontal cortex.  Nat Neurosci. 2001;4(1):95-102.PubMedGoogle ScholarCrossref
50.
Roesch  MR, Olson  CR.  Neuronal activity related to reward value and motivation in primate frontal cortex.  Science. 2004;304(5668):307-310.PubMedGoogle ScholarCrossref
51.
Rankin  KP, Salazar  A, Gorno-Tempini  ML,  et al.  Detecting sarcasm from paralinguistic cues: anatomic and cognitive correlates in neurodegenerative disease.  Neuroimage. 2009;47(4):2005-2015.PubMedGoogle ScholarCrossref
52.
Sollberger  M, Neuhaus  J, Ketelle  R,  et al.  Interpersonal traits change as a function of disease type and severity in degenerative brain diseases.  J Neurol Neurosurg Psychiatry. 2011;82(7):732-739.PubMedGoogle ScholarCrossref
53.
Sollberger  M, Rankin  KP, Miller  BL.  Social cognition.  Continuum (Minneap Minn). 2010;16(4 Behavioral Neurology):69-85.PubMedGoogle Scholar
Original Investigation
September 2016

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

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
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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