Frontotemporal Lobar Degeneration: A Clinical Approach

 

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Abstract

In this review, the authors outline a clinical approach to frontotemporal lobar degeneration (FTLD), a term coined to describe a pathology associated with atrophy of the frontal and temporal lobes commonly seen with abnormal protein aggregates. It accounts for ∼10% of pathologically confirmed dementias. The three clinical syndromes associated with FTLD are jointly classified as frontotemporal dementia (FTD) and include behavioral variant frontotemporal dementia (bvFTD), nonfluent-agrammatic primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA; left: l-svPPA and right: r-svPPA). All syndromes have differential impairment in behavioral (bvFTD; r-svPPA), executive (bvFTD; nfvPPA), and language (nfvPPA; svPPA) functions early in the disease course. With all three there is relative sparing of short-term memory and visuospatial abilities early on, and with the two language syndromes, nfvPPA and svPPA, behavior is also intact. Symptoms are associated with specific atrophy patterns, lending unique imaging signatures to each syndrome (frontal: bvFTD and nfvPPA; temporal: svPPA). Common proteinopathies involve accumulation of tau, transactive response DNA binding protein 43, and fusion in sarcoma protein. Parkinsonism presents in all syndromes, especially cases with tau pathology and MAPT or GRN mutations. nfvPPA often has corticobasal degeneration or progressive supranuclear palsy as the underlying neuropathological substrate. bvFTD co-occurs with motor neuron disease in ∼15% of cases, and many such cases are due to C9Orf72 mutations. Other common genetic mutations in FTLD involve GRN and MAPT. Behavioral symptoms are best managed by selective serotonin reuptake inhibitors, while atypical antipsychotics should be used with caution given side effects. Promising etiologic treatments include anti-tau antibodies, antisense oligonucleotides, and progranulin enhancers.

• References

• 1 Mesulam MM. Primary progressive aphasia. Ann Neurol 2001; 49 (4) 425-432
  CrossrefPubMedGoogle Scholar
• 2 Rademakers R, Neumann M, Mackenzie IR. Advances in understanding the molecular basis of frontotemporal dementia. Nat Rev Neurol 2012; 8 (8) 423-434
  PubMedGoogle Scholar
• 3 Gorno-Tempini ML, Hillis AE, Weintraub S , et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76 (11) 1006-1014
  CrossrefPubMedGoogle Scholar
• 4 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
  CrossrefPubMedGoogle Scholar
• 5 Pick A. Über die Beziehungen der senilen Hirnatrophie zur Aphasie. Prager Medicinische Wochenschrift 1892; 17: 165-167
  PubMedGoogle Scholar
• 6 Constantinidis J, Richard J, Tissot R. Pick's disease. Histological and clinical correlations. Eur Neurol 1974; 11 (4) 208-217
  CrossrefPubMedGoogle Scholar
• 7 Delay J, Brion S, Escourolle R. Limites et conception actuelle de la maladie de Pick; son diagnostic différentiel. Ann Med Psychol (Paris) 1957; 115 (4) 609-634
  PubMedGoogle Scholar
• 8 Mesulam MM. Slowly progressive aphasia without generalized dementia. Ann Neurol 1982; 11 (6) 592-598
  CrossrefPubMedGoogle Scholar
• 9 Hutton M, Lendon CL, Rizzu P , et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998; 393 (6686) 702-705
  CrossrefPubMedGoogle Scholar
• 10 Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A 1998; 95 (13) 7737-7741
  CrossrefPubMedGoogle Scholar
• 11 Baker M, Mackenzie IR, Pickering-Brown SM , et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006; 442 (7105) 916-919
  CrossrefPubMedGoogle Scholar
• 12 Cruts M, Gijselinck I, van der Zee J , et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006; 442 (7105) 920-924
  CrossrefPubMedGoogle Scholar
• 13 DeJesus-Hernandez M, Mackenzie IR, Boeve BF , et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011; 72 (2) 245-256
  CrossrefPubMedGoogle Scholar
• 14 Renton AE, Majounie E, Waite A , et al; ITALSGEN Consortium. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011; 72 (2) 257-268
  CrossrefPubMedGoogle Scholar
• 15 Arai T, Hasegawa M, Akiyama H , et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 2006; 351 (3) 602-611
  CrossrefPubMedGoogle Scholar
• 16 Neumann M, Sampathu DM, Kwong LK , et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006; 314 (5796) 130-133
  CrossrefPubMedGoogle Scholar
• 17 Knopman DS, Roberts RO. Estimating the number of persons with frontotemporal lobar degeneration in the US population. J Mol Neurosci 2011; 45 (3) 330-335
  CrossrefPubMedGoogle Scholar
• 18 Snowden JS, Neary D, Mann DM. Frontotemporal dementia. Br J Psychiatry 2002; 180: 140-143
  CrossrefPubMedGoogle Scholar
• 19 Hodges JR, Davies R, Xuereb J, Kril J, Halliday G. Survival in frontotemporal dementia. Neurology 2003; 61 (3) 349-354
  CrossrefPubMedGoogle Scholar
• 20 Ioannidis P, Konstantinopoulou E, Maiovis P, Karacostas D. The frontotemporal dementias in a tertiary referral center: classification and demographic characteristics in a series of 232 cases. J Neurol Sci 2012; 318 (1-2) 171-173
  CrossrefPubMedGoogle Scholar
• 21 Johnson JK, Diehl J, Mendez MF , et al. Frontotemporal lobar degeneration: demographic characteristics of 353 patients. Arch Neurol 2005; 62 (6) 925-930
  CrossrefPubMedGoogle Scholar
• 22 Roberson ED, Hesse JH, Rose KD , et al. Frontotemporal dementia progresses to death faster than Alzheimer disease. Neurology 2005; 65 (5) 719-725
  CrossrefPubMedGoogle Scholar
• 23 Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseases target large-scale human brain networks. Neuron 2009; 62 (1) 42-52
  CrossrefPubMedGoogle Scholar
• 24 Kfoury N, Holmes BB, Jiang H, Holtzman DM, Diamond MI. Trans-cellular propagation of tau aggregation by fibrillar species. J Biol Chem 2012; 287 (23) 19440-19451
  CrossrefPubMedGoogle Scholar
• 25 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
  CrossrefPubMedGoogle Scholar
• 26 Brambati SM, Rankin KP, Narvid J , et al. Atrophy progression in semantic dementia with asymmetric temporal involvement: a tensor-based morphometry study. Neurobiol Aging 2009; 30 (1) 103-111
  CrossrefPubMedGoogle Scholar
• 27 Seeley WW, Bauer AM, Miller BL , et al. The natural history of temporal variant frontotemporal dementia. Neurology 2005; 64 (8) 1384-1390
  CrossrefPubMedGoogle Scholar
• 28 Gorno-Tempini ML, Dronkers NF, Rankin KP , et al. Cognition and anatomy in three variants of primary progressive aphasia. Ann Neurol 2004; 55 (3) 335-346
  CrossrefPubMedGoogle Scholar
• 29 Lu PH, Mendez MF, Lee GJ , et al. Patterns of brain atrophy in clinical variants of frontotemporal lobar degeneration. Dement Geriatr Cogn Disord 2013; 35 (1-2) 34-50
  CrossrefPubMedGoogle Scholar
• 30 Seeley WW, Crawford R, Rascovsky K , et al. Frontal paralimbic network atrophy in very mild behavioral variant frontotemporal dementia. Arch Neurol 2008; 65 (2) 249-255
  CrossrefPubMedGoogle Scholar
• 31 Rosen HJ, Gorno-Tempini ML, Goldman WP , et al. Patterns of brain atrophy in frontotemporal dementia and semantic dementia. Neurology 2002; 58 (2) 198-208
  CrossrefPubMedGoogle Scholar
• 32 Knibb JA, Xuereb JH, Patterson K, Hodges JR. Clinical and pathological characterization of progressive aphasia. Ann Neurol 2006; 59 (1) 156-165
  CrossrefPubMedGoogle Scholar
• 33 Marczinski CA, Davidson W, Kertesz A. A longitudinal study of behavior in frontotemporal dementia and primary progressive aphasia. Cogn Behav Neurol 2004; 17 (4) 185-190
  PubMedGoogle Scholar
• 34 Liu W, Miller BL, Kramer JH , et al. Behavioral disorders in the frontal and temporal variants of frontotemporal dementia. Neurology 2004; 62 (5) 742-748
  CrossrefPubMedGoogle Scholar
• 35 Le Ber I, Guedj E, Gabelle A , et al; French research network on FTD/FTD-MND. Demographic, neurological and behavioural characteristics and brain perfusion SPECT in frontal variant of frontotemporal dementia. Brain 2006; 129 (Pt 11) 3051-3065
  CrossrefPubMedGoogle Scholar
• 36 Kramer JH, Jurik J, Sha SJ , et al. Distinctive neuropsychological patterns in frontotemporal dementia, semantic dementia, and Alzheimer disease. Cogn Behav Neurol 2003; 16 (4) 211-218
  CrossrefPubMedGoogle Scholar
• 37 Mendez MF, Shapira JS. Loss of emotional insight in behavioral variant frontotemporal dementia or “frontal anosodiaphoria”. Conscious Cogn 2011; 20 (4) 1690-1696
  CrossrefPubMedGoogle Scholar
• 38 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
  CrossrefPubMedGoogle Scholar
• 39 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
  CrossrefPubMedGoogle Scholar
• 40 Rohrer JD, Warren JD. Phenotypic signatures of genetic frontotemporal dementia. Curr Opin Neurol 2011; 24 (6) 542-549
  CrossrefPubMedGoogle Scholar
• 41 Janssens J, Van Broeckhoven C. Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD-ALS spectrum disorders. Hum Mol Genet 2013; 22 (R1) R77-R87
  CrossrefPubMedGoogle Scholar
• 42 Miller ZA, Rankin KP, Graff-Radford NR , et al. TDP-43 frontotemporal lobar degeneration and autoimmune disease. J Neurol Neurosurg Psychiatry 2013; 84 (9) 956-962
  CrossrefPubMedGoogle Scholar
• 43 Miller ZA, Mandelli ML, Rankin KP , et al. Handedness and language learning disability differentially distribute in progressive aphasia variants. Brain 2013; 136 (Pt 11) 3461-3473
  CrossrefPubMedGoogle Scholar
• 44 Smith BN, Newhouse S, Shatunov A , et al. The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder. Eur J Hum Genet 2013; 21 (1) 102-108
  CrossrefPubMedGoogle Scholar
• 45 van Blitterswijk M, DeJesus-Hernandez M, Niemantsverdriet E , et al. Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study. Lancet Neurol 2013; 12 (10) 978-988
  CrossrefPubMedGoogle Scholar
• 46 Catani M, Mesulam MM, Jakobsen E , et al. A novel frontal pathway underlies verbal fluency in primary progressive aphasia. Brain 2013; 136 (Pt 8) 2619-2628
  CrossrefPubMedGoogle Scholar
• 47 Ash S, Evans E, O'Shea J , et al. Differentiating primary progressive aphasias in a brief sample of connected speech. Neurology 2013; 81 (4) 329-336
  CrossrefPubMedGoogle Scholar
• 48 Thompson SA, Patterson K, Hodges JR. Left/right asymmetry of atrophy in semantic dementia: behavioral-cognitive implications. Neurology 2003; 61 (9) 1196-1203
  CrossrefPubMedGoogle Scholar
• 49 Armstrong MJ, Litvan I, Lang AE , et al. Criteria for the diagnosis of corticobasal degeneration. Neurology 2013; 80 (5) 496-503
  CrossrefPubMedGoogle Scholar
• 50 Litvan I, Agid Y, Calne D , et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996; 47 (1) 1-9
  CrossrefPubMedGoogle Scholar
• 51 Lee SE, Rabinovici GD, Mayo MC , et al. Clinicopathological correlations in corticobasal degeneration. Ann Neurol 2011; 70 (2) 327-340
  CrossrefPubMedGoogle Scholar
• 52 Boeve BF, Hutton M. Refining frontotemporal dementia with parkinsonism linked to chromosome 17: introducing FTDP-17 (MAPT) and FTDP-17 (PGRN). Arch Neurol 2008; 65 (4) 460-464
  CrossrefPubMedGoogle Scholar
• 53 Borroni B, Archetti S, Del Bo R , et al. TARDBP mutations in frontotemporal lobar degeneration: frequency, clinical features, and disease course. Rejuvenation Res 2010; 13 (5) 509-517
  CrossrefPubMedGoogle Scholar
• 54 Lee SE. Guam dementia syndrome revisited in 2011. Curr Opin Neurol 2011; 24 (6) 517-524
  CrossrefPubMedGoogle Scholar
• 55 Elamin M, Pender N, Hardiman O, Abrahams S. Social cognition in neurodegenerative disorders: a systematic review. J Neurol Neurosurg Psychiatry 2012; 83 (11) 1071-1079
  CrossrefPubMedGoogle Scholar
• 56 Santillo AF, Mårtensson J, Lindberg O , et al. Diffusion tensor tractography versus volumetric imaging in the diagnosis of behavioral variant frontotemporal dementia. PLoS ONE 2013; 8 (7) e66932
  CrossrefPubMedGoogle Scholar
• 57 Dopper EG, Rombouts SA, Jiskoot LC , et al. Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia. Neurology 2013; 80 (9) 814-823
  CrossrefPubMedGoogle Scholar
• 58 Houlden H, Baker M, Morris HR , et al. Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology 2001; 56 (12) 1702-1706
  CrossrefPubMedGoogle Scholar
• 59 Finch N, Carrasquillo MM, Baker M , et al. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology 2011; 76 (5) 467-474
  CrossrefPubMedGoogle Scholar
• 60 van Blitterswijk M, Mullen B, Nicholson AM , et al. TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta Neuropathol 2014; 127 (3) 397-406 [Epub ahead of print]
  CrossrefPubMedGoogle Scholar
• 61 Bian H, Van Swieten JC, Leight S , et al. CSF biomarkers in frontotemporal lobar degeneration with known pathology. Neurology 2008; 70 (19 Pt 2) 1827-1835
  CrossrefPubMedGoogle Scholar
• 62 Johnson KA, Minoshima S, Bohnen NI , et al. Appropriate use criteria for amyloid PET: A report of the amyloid imaging task force, the society of nuclear medicine and molecular imaging, and the Alzheimer's association. J Nucl Med 2013; 54 (3) 476-490
  CrossrefPubMedGoogle Scholar
• 63 Maruyama M, Shimada H, Suhara T , et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 2013; 79 (6) 1094-1108
  CrossrefPubMedGoogle Scholar
• 64 Herrmann N, Black SE, Chow T, Cappell J, Tang-Wai DF, Lanctôt KL. Serotonergic function and treatment of behavioral and psychological symptoms of frontotemporal dementia. Am J Geriatr Psychiatry 2012; 20 (9) 789-797
  CrossrefPubMedGoogle Scholar
• 65 Swartz JR, Miller BL, Lesser IM, Darby AL. Frontotemporal dementia: treatment response to serotonin selective reuptake inhibitors. J Clin Psychiatry 1997; 58 (5) 212-216
  CrossrefPubMedGoogle Scholar
• 66 Moretti R, Torre P, Antonello RM, Cazzato G, Bava A. Effects of selegiline on fronto-temporal dementia: a neuropsychological evaluation. Int J Geriatr Psychiatry 2002; 17 (4) 391-392
  CrossrefPubMedGoogle Scholar
• 67 Moretti R, Torre P, Antonello RM, Cazzato G, Griggio S, Bava A. Olanzapine as a treatment of neuropsychiatric disorders of Alzheimer's disease and other dementias: a 24-month follow-up of 68 patients. Am J Alzheimers Dis Other Demen 2003; 18 (4) 205-214
  CrossrefPubMedGoogle Scholar
• 68 Moretti R, Torre P, Antonello RM, Cazzato G, Bava A. Frontotemporal dementia: paroxetine as a possible treatment of behavior symptoms. A randomized, controlled, open 14-month study. Eur Neurol 2003; 49 (1) 13-19
  CrossrefPubMedGoogle Scholar
• 69 Moretti R, Torre P, Antonello RM, Cattaruzza T, Cazzato G, Bava A. Rivastigmine in frontotemporal dementia: an open-label study. Drugs Aging 2004; 21 (14) 931-937
  CrossrefPubMedGoogle Scholar
• 70 Mendez MF, Shapira JS, Miller BL. Stereotypical movements and frontotemporal dementia. Mov Disord 2005; 20 (6) 742-745
  CrossrefPubMedGoogle Scholar
• 71 Ikeda M, Shigenobu K, Fukuhara R , et al. Efficacy of fluvoxamine as a treatment for behavioral symptoms in frontotemporal lobar degeneration patients. Dement Geriatr Cogn Disord 2004; 17 (3) 117-121
  CrossrefPubMedGoogle Scholar
• 72 Lebert F, Stekke W, Hasenbroekx C, Pasquier F. Frontotemporal dementia: a randomised, controlled trial with trazodone. Dement Geriatr Cogn Disord 2004; 17 (4) 355-359
  CrossrefPubMedGoogle Scholar
• 73 Mendez MF, Shapira JS, McMurtray A, Licht E. Preliminary findings: behavioral worsening on donepezil in patients with frontotemporal dementia. Am J Geriatr Psychiatry 2007; 15 (1) 84-87
  CrossrefPubMedGoogle Scholar
• 74 Kimura T, Takamatsu J. Pilot study of pharmacological treatment for frontotemporal dementia: risk of donepezil treatment for behavioral and psychological symptoms. Geriatr Gerontol Int 2013; 13 (2) 506-507
  CrossrefPubMedGoogle Scholar
• 75 Kertesz A, Morlog D, Light M , et al. Galantamine in frontotemporal dementia and primary progressive aphasia. Dement Geriatr Cogn Disord 2008; 25 (2) 178-185
  CrossrefPubMedGoogle Scholar
• 76 Huey ED, Garcia C, Wassermann EM, Tierney MC, Grafman J. Stimulant treatment of frontotemporal dementia in 8 patients. J Clin Psychiatry 2008; 69 (12) 1981-1982
  CrossrefPubMedGoogle Scholar
• 77 Reed DA, Johnson NA, Thompson C, Weintraub S, Mesulam MM. A clinical trial of bromocriptine for treatment of primary progressive aphasia. Ann Neurol 2004; 56 (5) 750
  PubMedGoogle Scholar
• 78 Rahman S, Robbins TW, Hodges JR , et al. Methylphenidate ('Ritalin') can ameliorate abnormal risk-taking behavior in the frontal variant of frontotemporal dementia. Neuropsychopharmacology 2006; 31 (3) 651-658
  CrossrefPubMedGoogle Scholar
• 79 Diehl-Schmid J, Förstl H, Perneczky R, Pohl C, Kurz A. A 6-month, open-label study of memantine in patients with frontotemporal dementia. Int J Geriatr Psychiatry 2008; 23 (7) 754-759
  CrossrefPubMedGoogle Scholar
• 80 Boxer AL, Knopman DS, Kaufer DI , et al. Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2013; 12 (2) 149-156
  CrossrefPubMedGoogle Scholar
• 81 Boxer AL, Lipton AM, Womack K , et al. An open-label study of memantine treatment in 3 subtypes of frontotemporal lobar degeneration. Alzheimer Dis Assoc Disord 2009; 23 (3) 211-217
  CrossrefPubMedGoogle Scholar
• 82 Vercelletto M, Boutoleau-Bretonnière C, Volteau C , et al; French research network on frontotemporal dementia. Memantine in behavioral variant frontotemporal dementia: negative results. J Alzheimers Dis 2011; 23 (4) 749-759
  PubMedGoogle Scholar
• 83 Boxer AL, Gold M, Huey E , et al. Frontotemporal degeneration, the next therapeutic frontier: molecules and animal models for frontotemporal degeneration drug development. Alzheimers Dement 2013; 9 (2) 176-188
  CrossrefPubMedGoogle Scholar
• 84 Yanamandra K, Kfoury N, Jiang H , et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 2013; 80 (2) 402-414
  CrossrefPubMedGoogle Scholar
• 85 Lagier-Tourenne C, Baughn M, Rigo F , et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A 2013; 110 (47) E4530-E4539
  CrossrefPubMedGoogle Scholar
• 86 Decker DA, Heilman KM. Steroid treatment of primary progressive aphasia. Arch Neurol 2008; 65 (11) 1533-1535
  CrossrefPubMedGoogle Scholar