Behavioural-variant frontotemporal dementia: An update

Piguet, Olivier; Hodges, John R.

doi:10.1590/S1980-57642013DN70100003

ABSTRACT

Behavioural-variant frontotemporal dementia (bvFTD) is characterised by insidious changes in personality and interpersonal conduct that reflect progressive disintegration of the neural circuits involved in social cognition, emotion regulation, motivation and decision making. The underlying pathology is heterogeneous and classified according to the presence of intraneuronal inclusions of tau, TDP-43 or occasionally FUS. Biomarkers to detect these histopathological changes in life are increasingly important with the development of disease-modifying drugs. Gene mutations have been found which collectively account for around 10-20% of cases including a novel hexanucleotide repeat on chromosome 9 (C9orf72). The recently reviewed International Consensus Criteria for bvFTD propose three levels of diagnostic certainly: possible, probable and definite. Detailed history taking from family members to elicit behavioural features underpins the diagnostic process with support from neuropsychological testing designed to detect impairment in decision-making, emotion processing and social cognition. Brain imaging is important for increasing the level of diagnosis certainty. Carer education and support remain of paramount importance.

Key words:
frontotemporal dementia; genetics; cognition; social cognition; neuroimaging

RESUMO

A demência frontotemporal-variante comportamental (DFTvc) é caracterizada por mudanças insidiosas de personalidade e conduta interpessoal, que refletem a desintegração progressiva de circuitos neurais envolvidos em cognição social, regulação emocional, motivação e tomada de decisão. O substrato patológico é heterogêneo e classificado de acordo com a presença de inclusões intraneuronais de proteína tau, TDP-43 ou, ocasionalmente, de FUS. Biomarcadores capazes de detectar estas alterações histopatológicas durante a vida vêm ganhando importância com o desenvolvimento de drogas específicas modificadoras da doença. Algumas mutações genéticas já foram encontradas, sendo em conjunto responsáveis por 10-20% dos casos, incluindo a recentemente descrita repetição de hexanucleotídeo no cromossomo 9 (C9orf72). A versão revisada dos Critérios Internacionais do Consenso em DFTvc propõe três níveis de certeza diagnóstica: possível, provável e definida. História clínica detalhada obtida com familiares, para identificar as alterações de comportamento características, auxilia no diagnóstico, juntamente com o apoio de avaliação neuropsicológica dirigida à detecção de comprometimento em tarefas de tomada de decisão, processamento emocional e cognição social. A neuroimagem é importante para aumentar o grau de certeza diagnóstica. Educação e suporte dos cuidadores continuam sendo medidas de extrema relevância.

Palavras-chave:
demência frontotemporal; genética; cognição; cognição social; neuroimagem

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REFERENCES

Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology 2002;58:1615-1621.
Rosso SM, Donker Kaat L, Baks T, et al. Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain 2003;126:2016-2022.
Grossman M. Primary progressive aphasia: clinicopathological correlations. Nat Rev Neurol 2010;6:88-97.
Hodges JR, Patterson K. Semantic dementia: a unique clinicopathological syndrome.Lancet Neurol 2007;6:1004-1014.
Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology1998; 51:1546-1554.
Lillo P, Garcin B, Hornberger M, Bak TH, Hodges JR. Neurobehavioral features in frontotemporal dementia with amyotrophic lateral sclerosis. Arch Neurol 2010;67:826-830.
Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology2002;59:1077-1079.
Lillo P, Mioshi E, Zoing MC, Kiernan MC, Hodges JR. How common are behavioural changes in amyotrophic lateral sclerosis? Amyotroph Lateral Scler 2011;12:45-51.
Kertesz A, McMonagle P, Blair M, Davidson W, Munoz DG. The evolution and pathology of frontotemporal dementia. Brain 2005;128:1996-2005.
Cairns NJ, Bigio EH, Mackenzie IR, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration Acta Neuropathol (Berlin) 20076;114:5-22.
Broe M, Hodges JR, Schofield E, Shepherd CE, Kril JJ, Halliday GM. Staging disease severity in pathologically confirmed cases of frontotemporal dementia. Neurology2003;60:1005-1011.
Kril JJ, Macdonald V, Patel S, Png F, Halliday GM. Distribution of brain atrophy in behavioral variant frontotemporal dementia J Neurol Sci 2005;232:83-90.
Kersaitis C, Halliday GM, Kril JJ. Regional and cellular pathology in frontotemporal dementia: relationship to stage of disease in cases with and without Pick bodies Acta Neuropathol 2004;108:515-523.
Mackenzie IR, Neumann M, Bigio EH, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol2010;119:1-4.
Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR. A new subtype of frontotemporal lobar degeneration with FUS pathology Brain2009;132:2922-2931.
Hodges JR, Davies RR, Xuereb JH, et al. Clinicopathological correlates in frontotemporal dementia Annals of Neurology2004;56:399-406.
Shi J, Shaw CL, Du Plessis D, et al. Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation. Acta Neuropathol2005;110:501-512.
Seelaar H, Klijnsma KY, de Koning I, et al. Frequency of ubiquitin and FUS-positive TDP-43-negative frontotemporal lobar degeneration. J Neurol 2010;257:747-753.
Rohrer JD, Guerreiro R, Vandrovcova J, et al. The heritability and genetics of frontotemporal lobar degeneration. Neurology2009;73: 1451-1456.
Vance C, Al-Chalabi A, Ruddy D, et al. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p132-213 Brain2006;129:868-876.
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: 245-256
Renton AE, Majounie E, Waite A, et al.A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron2011;72:257-268.
Hodges J. Familial frontotemporal dementia and amyotrophic lateral sclerosis associated with the C9ORF72 hexanucleotide repeat. Brain 2012;135:652-655.
Dobson-Stone C, Hallupp M, Bartley L, et al.C9ORF72 repeat expansion in clinical and neuropathologic frontotemporal dementia cohorts. Neurology2012;79:995-1001.
Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain2012;135:693-708.
Schofield EC, Halliday GM, Kwok J, Loy C, Double KL,Hodges JR. Low serum progranulin predicts the presence of mutations: a prospective study. J Alzheimers Dis 2010;22:981-984.
Benajiba L, Le Ber I, Camuzat A, et al.TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration Ann Neurol 2009;65:470-473.
Blair IP, Williams KL, Warraich ST, et al. FUS mutations in amyotrophic lateral sclerosis: clinical pathological neurophysiological and genetic analysis. J NeurolNeurosurg Psychiatry 2010;81:639-645.
Watts GD, Wymer J, Kovach MJ, et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 2004;36: 377-381.
Parkinson N, Ince PG, Smith MO, et al. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology2006;67:1074-1077.
van der Zee J, Urwin H, Engelborghs S, et al.CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro. Hum Mol Genet 2008;17: 313-322.
Huey ED, Goveia EN, Paviol S.Executive dysfunction in frontotemporal dementia and corticobasal syndrome. Neurology2009;72:453-459.
Kipps CM, Mioshi E, Hodges JR. Emotion social functioning and activities of daily living in frontotemporal dementia. Neurocase 2009; 15: 182-189.
Seeley WW. Selective functional regional and neuronal vulnerability in frontotemporal dementia Curr Opin Neurol 2008;21:701-707.
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DAGornbein J. (1994) The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology1944;44: 2308-2314.
Bozeat S, Gregory CA, Ralph MA, Hodges JR. Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer's disease? J NeurolNeurosurg Psychiatry 2000;69:178-186.
Kertesz A, Davidson W,Fox H.Frontal behavioral inventory: diagnostic criteria for frontal lobe dementia. Can J Neurol Sci1997;24:29-36.
Loy C T, Kril JJ, Trollor JN, et al.The case of a 48 year-old woman with bizarre and complex delusions. Nat Rev Neurol 2010;6:175-179.
Liu W, Miller BL, Kramer JH.Behavioral disorders in the frontal and temporal variants of frontotemporal dementia Neurology2004;62:742-748.
Diehl-Schmid J, Pohl C, Perneczky R, Forstl H,Kurz A.Behavioral disturbances in the course of frontotemporal dementia. Dement Geriatr Cogn Disord 2006;22:352-357.
Srikanth S, Nagaraja AV,Ratnavalli E.Neuropsychiatric symptoms in dementia-frequency relationship to dementia severity and comparison in Alzheimer's disease vascular dementia and frontotemporal dementia. J Neurol Sci2005;236:43-48.
Pasquier F, Lebert F, Lavenu I,Guillaume B.The clinical picture of frontotemporal dementia: diagnosis and follow-up. Dement Geriatr Cogn Disord1999;10( Suppl 1):10-14.
Kipps CM, Nestor PJ, Fryer TD, Hodges JR. Behavioural variant frontotemporal dementia: not all it seems? Neurocase2007;13:237-247.
Davies RR, Kipps CM, Mitchell J, Kril JJ, Halliday GM, Hodges JR. Progression in frontotemporal dementia: identifying a benign behavioral variant by magnetic resonance imaging. Arch Neurol2006;63: 1627-1631.
Hornberger M, Shelley BP, Kipps CM, Piguet O, Hodges JR. Can progressive and non-progressive behavioral variant frontotemporal dementia be distinguished at presentation? J NeurolNeurosurg Psychiatry 2009;80:591-593.
Piguet O, Hornberger M, Shelley BP, Kipps CMHodges JR.Sensitivity of current criteria for the diagnosis of behavioral variant frontotemporal dementia. Neurology2009;72:732-737.
Kipps CM, Hodges JR, Fryer TD,Nestor PJ.Combined magnetic resonance imaging and positron emission tomography brain imaging in behavioural variant frontotemporal degeneration: refining the clinical phenotype. Brain2009;132:2566-2578.
Khan BK, Yokoyama JS, Takada LT. Atypical slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. J NeurolNeurosurg Psychiatry 2012;83:358-364.
Mioshi E, Kipps CM, Dawson K, Mitchell J, Graham A, Hodges JR. Activities of daily living in frontotemporal dementia and Alzheimer disease Neurology2007;68:2077-2084
Kipps CM, Nestor PJ, Dawson CE, Mitchell J, Hodges JR.Measuring progression in frontotemporal dementia: Implications for therapeutic interventions. Neurology 2008;70:2046-2052.
Giovagnoli AR, Erbetta A, Reati F,Bugiani O. Differential neuropsychological patterns of frontal variant frontotemporal dementia and Alzheimer's disease in a study of diagnostic concordance. Neuropsychologia 2008;46:1495-1504.
Hornberger M, Piguet O, Kipps C, Hodges JR. Executive function in progressive and nonprogressive behavioral variant frontotemporal dementia. Neurology 2008;71:1481-1488.
Gleichgerrcht E, Torralva T, Roca M,Manes F. Utility of an abbreviated version of the executive and social cognition battery in the detection of executive deficits in early behavioral variant frontotemporal dementia patients. J Int Neuropsychol Soc 2010;19:1-8.
Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain2011;34:2456-2477.
Graham A, Davies R, Xuereb J, et al. Pathologically proven frontotemporal dementia presenting with severe amnesia. Brain2005;128:597-605.
Hornberger M,. Piguet O Episodic memory in frontotemporal dementia: a critical review. Brain2012;135:678-692.
Hornberger M, Piguet O, Graham AJ, Nestor PJ, Hodges JR. How preserved is episodic memory in behavioral variant frontotemporal dementia?Neurology2010;74:472-479.
Irish M, Hornberger M, Lah S, et al. Profiles of recent autobiographical memory retrieval in semantic dementia behavioural-variant frontotemporal dementia and Alzheimer's disease. Neuropsychologia2011; 49:2694-2702.
Irish M, Piguet O, Hodges JR.Self-projection and the default network in frontotemporal dementia. Nat Rev Neurol 2011;8:152-161.
Fellows LK, Farah MJ. Ventromedial frontal cortex mediates affective shifting in humans: evidence from a reversal learning paradigm. Brain2003;126:1830-1837.
Bertoux M, Funkiewiez A, O'Callaghan C, Dubois B.. Hornberger M Sensitivity and specificity of ventromedial prefrontal cortex tests in behavioral variant frontotemporal dementia. Alzheimers Dement 2012: S1552-5260(12)02499-5.
Torralva T, Roca M, Gleichgerrcht E, Bekinschtein T, Manes F. A neuropsychological battery to detect specific executive and social cognitive impairments in early frontotemporal dementia. Brain2009;132: 1299-1309.
Kumfor F,. Piguet O Disturbance of emotion processing in frontotemporal dementia: a synthesis of cognitive and neuroimaging findings. Neuropsychol Rev 2012;22:280 -297.
Rankin KP, Gorno-Tempini ML, Allison SC, et al. Structural anatomy of empathy in neurodegenerative disease Brain2006;129:2945-2956
Rankin KP, Salazar A, Gorno-Tempini ML, et al. Detecting sarcasm from paralinguistic cues: anatomic and cognitive correlates in neurodegenerative disease. NeuroImage 2009;47:2005-2015.
Snowden JS, Austin NA, Sembi S, Thompson JC, Craufurd D,Neary D. Emotion recognition in Huntington's disease and frontotemporal dementia. Neuropsychologia2008;46:2638-2649.
Hsieh S, Hodges JR,. Piguet O Recognition of positive vocalizations is impaired in behavioral-variant frontotemporal dementia. J Int Neuropsychol Soc2013; 1:1-5.
Hsieh S, Foxe D, Leslie F, Savage S, Piguet O, Hodges JR. Grief and joy: emotion word comprehension in the dementias. Neuropsychology 2012;26:624-630.
Omar R, Henley SM, Bartlett JW, et al. The structural neuroanatomy of music emotion recognition: evidence from frontotemporal lobar degeneration. NeuroImage2011;56:1814-1821.
Werner KH, Roberts NA, Rosen HJ, et al. Emotional reactivity and emotion recognition in frontotemporal lobar degeneration. Neurology 2007;69:148-155.
Sturm VE, Rosen HJ, Allison S, Miller BL,Levenson RW. Self-conscious emotion deficits in frontotemporal lobar degeneration. Brain2006; 129:2508-2516.
Sturm VE, Sollberger M, Seeley WW. Role of right pregenual anterior cingulate cortex in self-conscious emotional reactivity. Soc Cogn Affect Neurosci 2012 (Epub ahead of print).
Kumfor F, Miller L, Lah S, et al. Are you really angry? The effect of intensity on facial emotion recognition in frontotemporal dementia. Soc Neurosci 2011; 6:502-514.
Miller L A, Hsieh S, Lah S, Savage S, Hodges JR,. Piguet O One size does not fit all: Face emotion processing impairments in semantic dementia behavioural-variant frontotemporal dementia and Alzheimer's disease are mediated by distinct cognitive deficits. Behav Neurol 2012;25:53-60.
Fernandez-Duque D, Hodges SD, Baird JA, Black SE. Empathy in frontotemporal dementia and Alzheimer's disease. J Clin Exp Neuropsychol 2010;32:289-298.
Gregory C, Lough S, Stone V, et al. Theory of mind in patients with frontal variant frontotemporal dementia and Alzheimer's disease: theoretical and practical implications. Brain2002;125:752-764.
Lough S, Kipps CM, Treise C, Watson P, Blair JR, Hodges JR.Social reasoning emotion and empathy in frontotemporal dementia Neuropsychologia2006;44:950-958.
Shany-Ur T, Poorzand P, Grossman SN. Comprehension of insincere communication in neurodegenerative disease: lies sarcasm and theory of mind. Cortex 2012;48:1329-1341.
Mendez MF, Shapira JS. Altered emotional morality in frontotemporal dementia. Cogn Neuropsychiatry 2009;14:165-179.
Ibanez A, Manes F.Contextual social cognition and the behavioral variant of frontotemporal dementia. Neurology 2012;78:1354-1362.
Kipps CM, Nestor PJ, Acosta-Cabronero J, Arnold R, Hodges JR. Understanding social dysfunction in the behavioural variant of frontotemporal dementia: the role of emotion and sarcasm processing. Brain2009;132:592-603.
McDonald S, Flanagan S, Rollins J,Kinch J.TASIT: A new clinical tool for assessing social perception after traumatic brain injury. J Head Trauma Rehabil 2003;18:219-238.
Davatzikos C, Resnick SM, Wu X, Parmpi P, Clark CM. Individual patient diagnosis of AD and FTD via high-dimensional pattern classification of MRI. NeuroImage2008;41:1220-1227.
Hornberger M, Savage S, Hsieh S, Mioshi E, Piguet O, Hodges JR.Orbitofrontal dysfunction discriminates behavioral variant frontotemporal dementia from Alzheimer's disease. Dementia and Geriatric Cognitive Disorders 2010;30:547-552.
Seeley WW, Crawford R, Rascovsky K,et al. Frontal paralimbic network atrophy in very mild behavioral variant frontotemporal dementia. Arch Neurol2008;65:249-255.
Boccardi M, Sabattoli F, Laakso MP, et al. Frontotemporal dementia as a neural system disease. Neurobiol Aging 2005;26:37-44.
Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseases target large-scale human brain networks. Neuron2009;62:42-52.
Seeley WW, Carlin DA, Allman JM, et al. Early frontotemporal dementia targets neurons unique to apes and humans. Ann Neurol2006;60: 660-667.
Zhou J, Greicius MD, Gennatas ED, et al. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease. Brain2010;133:1352-1367.
Josephs KA, Whitwell JL, Parisi JE et al. Caudate atrophy on RI is a characteristic feature of FTLD-FUS. Eur J Neurol2010;17:969-975.
Whitwell JL, Josephs KA, Rossor MN, et al. Magnetic resonance imaging signatures of tissue pathology in frontotemporal dementia. Arch Neurol2005;62:1402-1408.
Pereira JM, Williams GB, Acosta-Cabronero J, et al. Atrophy patterns in histologic vs clinical groupings of frontotemporal lobar degeneration. Neurology 2009;72:1653-1660.
Barnes J, Whitwell JL, Frost C, Josephs KA, Rossor M, Fox NC. Measurements of the amygdala and hippocampus in pathologically confirmed Alzheimer disease and frontotemporal lobar degeneration. Arch Neurol2006;63:1434-1439.
Piguet O, Petersen A, Yin Ka Lam B, et al. MEating and hypothalamus changes in behavioral-variant frontotemporal dementia. Ann Neurol2011;69:312-319.
Filippi M, Agosta F, Scola E, et al. Functional network connectivity in the behavioral variant of frontotemporal dementia. Cortex2012:S0010-9452(12)00303-6.
Agosta F, Scola E, Canu E, et al. White matter damage in frontotemporal lobar degeneration spectrum. Cereb Cortex2012;22:2705-2714.
Chao LL, Schuff N, Clevenger EM, et al. Patterns of white matter atrophy in frontotemporal lobar degeneration. Arch Neurol2007;64:1619-1624.
Zhang Y, Tartaglia MC, Schuff N, et al. MRI signatures of brain macrostructural atrophy and microstructural degradation in frontotemporal lobar degeneration subtypes. J Alzheimers Dis2013;33:431-444.
Zhang Y, Schuff N, Du AT. White matter damage in frontotemporal dementia and Alzheimer's disease measured by diffusion MRI. Brain2009;132:2579-2592.
WhitwellJL, AvulaR, Senjem ML, et al. Gray and white matter water diffusion in the syndromic variants of frontotemporal dementia. Neurology 2010;74:1279-1287.
Varma AR, Adams W, Lloyd JJ et al. Diagnostic patterns of regional atrophy on MRI and regional cerebral blood flow change on SPECT in young onset patients with Alzheimer's disease frontotemporal dementia and vascular dementia. Acta Neurol Scand 2002;105:261-269.
Kanda T, Ishii K, Uemura T, Miyamoto N, et al. Comparison of grey matter and metabolic reductions in frontotemporal dementia using FDG-PET and voxel-based morphometric MR studies. Eur J Nucl Med Mol Imaging2008;35:2227-2234.
Engler H, Santillo AF, Wang SX, et al. In vivo amyloid imaging with PET in frontotemporal dementia. Eur J Nucl Med Mol Imaging2008;35:100-106.
Rowe CC, Ng S, Ackermann U, et al. Imaging beta-amyloid burden in aging and dementia. Neurology 2007;68:1718-1725.
Boxer AL, Boeve BF. Frontotemporal dementia treatment: current symptomatic therapies and implications of recent genetic biochemical and neuroimaging studies. Alzheimer Dis Assoc Disord 2007;21:S79-87.
Deakin JB, Rahman S, Nestor PJ, Hodges JR, Sahakian BJ. Paroxetine does not improve symptoms and impairs cognition in frontotemporal dementia: a double-blind randomized controlled trial. Psychopharmacology (Berl) 2004;172:400-408.
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 Neurol2003;49:13-19.
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 DisOther Demen 2003;18:205-214.
Moretti R, Torre P, Antonello RM, Cattaruzza T, Cazzato G, Bava A.Rivastigmine in frontotemporal dementia: an open-label study. Drugs Aging 2004;21:931-937.
Mendez MF, Shapira JS, McMurtray A, Licht E. Preliminary findings: behavioral worsening on donepezil in patients with frontotemporal dementia. Am J Geriatr Psychiatry 2007;15:84-87.
Boxer AL, Knopman DS, Kaufer DI, et al. Memantine in patients with frontotemporal lobar degeneration: a multicentre randomised double-blind placebo-controlled trial. Lancet Neurol2013;12:149-156.
Vercelletto M, Boutoleau-Bretonniere C, Volteau C, Puel M, Auriacombe S, Sarazin M. French research network on Frontotemporal dementiaMemantine in behavioral variant frontotemporal dementia: negative results. J Alzheimers Dis2011;23:749-759.
Mendez MF. Frontotemporal dementia: therapeutic interventions. Front Neurol Neurosci 2009;24:168-178.
Merrilees J, Klapper J, Murphy J, Lomen-Hoerth C, Miller BL. Cognitive and behavioral challenges in caring for patients with frontotemporal dementia and amyotrophic lateral sclerosis . Amyotroph Lateral Scler 2010;11:298-302.
Mioshi E, McKinnon C, Savage S, O'Connor CM, Hodges JR.Improving Burden and Coping Skills in Frontotemporal Dementia Caregivers: A Pilot Study. Alzheimer Dis Assoc Disord2012 (Epub ahead of print).
Boutoleau-Bretonniere C, Vercelletto M, Volteau C, Renou P, Lamy E. Zarit burden inventory and activities of daily living in the behavioral variant of frontotemporal dementia. Dement Geriatr Cogn Disord2008; 25:272-277.
Mioshi E, Bristow M, Cook R, Hodges JR. Factors underlying caregiver stress in frontotemporal dementia and Alzheimer's disease. Dement Geriatr Cogn Disord2009;27:76-81.
Riedijk SR, De Vugt ME, Duivenvoorden HJ, et al. Caregiver burden health-related quality of life and coping in dementia caregivers: a comparison of frontotemporal dementia and Alzheimer's disease. Dement Geriatr Cogn Disord2006;22:405-412.
Miller L A, Mioshi E, Savage S, Lah S, Hodges JR,. Piguet O Identifying cognitive and demographic variables that contribute to carer urden in dementia. Dem Ger Cogn Disord 2013 (In press)
Mioshi E, Foxe D, Leslie F, Savage S, et al. The Impact of Dementia Severity on Caregiver Burden in Frontotemporal Dementia and Alzheimer Disease. Alzheimer Dis Assoc Disord2013 (In Press).

Publication Dates

Publication in this collection
Jan-Mar 2013

History

Received
27 Dec 2012
Accepted
28 Feb 2013

This is an open-access article distributed under the terms of the Creative Commons Attribution License

[1] Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal dementia. Neurology 2002;58:1615-1621.

[2] Rosso SM, Donker Kaat L, Baks T, et al. Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain 2003;126:2016-2022.

[3] Grossman M. Primary progressive aphasia: clinicopathological correlations. Nat Rev Neurol 2010;6:88-97.

[4] Hodges JR, Patterson K. Semantic dementia: a unique clinicopathological syndrome.Lancet Neurol 2007;6:1004-1014.

[5] Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology1998; 51:1546-1554.

[6] Lillo P, Garcin B, Hornberger M, Bak TH, Hodges JR. Neurobehavioral features in frontotemporal dementia with amyotrophic lateral sclerosis. Arch Neurol 2010;67:826-830.

[7] Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology2002;59:1077-1079.

[8] Lillo P, Mioshi E, Zoing MC, Kiernan MC, Hodges JR. How common are behavioural changes in amyotrophic lateral sclerosis? Amyotroph Lateral Scler 2011;12:45-51.

[9] Kertesz A, McMonagle P, Blair M, Davidson W, Munoz DG. The evolution and pathology of frontotemporal dementia. Brain 2005;128:1996-2005.

[10] Cairns NJ, Bigio EH, Mackenzie IR, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration Acta Neuropathol (Berlin) 20076;114:5-22.

[11] Broe M, Hodges JR, Schofield E, Shepherd CE, Kril JJ, Halliday GM. Staging disease severity in pathologically confirmed cases of frontotemporal dementia. Neurology2003;60:1005-1011.

[12] Kril JJ, Macdonald V, Patel S, Png F, Halliday GM. Distribution of brain atrophy in behavioral variant frontotemporal dementia J Neurol Sci 2005;232:83-90.

[13] Kersaitis C, Halliday GM, Kril JJ. Regional and cellular pathology in frontotemporal dementia: relationship to stage of disease in cases with and without Pick bodies Acta Neuropathol 2004;108:515-523.

[14] Mackenzie IR, Neumann M, Bigio EH, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol2010;119:1-4.

[15] Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR. A new subtype of frontotemporal lobar degeneration with FUS pathology Brain2009;132:2922-2931.

[16] Hodges JR, Davies RR, Xuereb JH, et al. Clinicopathological correlates in frontotemporal dementia Annals of Neurology2004;56:399-406.

[17] Shi J, Shaw CL, Du Plessis D, et al. Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation. Acta Neuropathol2005;110:501-512.

[18] Seelaar H, Klijnsma KY, de Koning I, et al. Frequency of ubiquitin and FUS-positive TDP-43-negative frontotemporal lobar degeneration. J Neurol 2010;257:747-753.

[19] Rohrer JD, Guerreiro R, Vandrovcova J, et al. The heritability and genetics of frontotemporal lobar degeneration. Neurology2009;73: 1451-1456.

[20] Vance C, Al-Chalabi A, Ruddy D, et al. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p132-213 Brain2006;129:868-876.

[21] 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: 245-256

[22] Renton AE, Majounie E, Waite A, et al.A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron2011;72:257-268.

[23] Hodges J. Familial frontotemporal dementia and amyotrophic lateral sclerosis associated with the C9ORF72 hexanucleotide repeat. Brain 2012;135:652-655.

[24] Dobson-Stone C, Hallupp M, Bartley L, et al.C9ORF72 repeat expansion in clinical and neuropathologic frontotemporal dementia cohorts. Neurology2012;79:995-1001.

[25] Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain2012;135:693-708.

[26] Schofield EC, Halliday GM, Kwok J, Loy C, Double KL,Hodges JR. Low serum progranulin predicts the presence of mutations: a prospective study. J Alzheimers Dis 2010;22:981-984.

[27] Benajiba L, Le Ber I, Camuzat A, et al.TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration Ann Neurol 2009;65:470-473.

[28] Blair IP, Williams KL, Warraich ST, et al. FUS mutations in amyotrophic lateral sclerosis: clinical pathological neurophysiological and genetic analysis. J NeurolNeurosurg Psychiatry 2010;81:639-645.

[29] Watts GD, Wymer J, Kovach MJ, et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 2004;36: 377-381.

[30] Parkinson N, Ince PG, Smith MO, et al. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology2006;67:1074-1077.

[31] van der Zee J, Urwin H, Engelborghs S, et al.CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro. Hum Mol Genet 2008;17: 313-322.

[32] Huey ED, Goveia EN, Paviol S.Executive dysfunction in frontotemporal dementia and corticobasal syndrome. Neurology2009;72:453-459.

[33] Kipps CM, Mioshi E, Hodges JR. Emotion social functioning and activities of daily living in frontotemporal dementia. Neurocase 2009; 15: 182-189.

[34] Seeley WW. Selective functional regional and neuronal vulnerability in frontotemporal dementia Curr Opin Neurol 2008;21:701-707.

[35] Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DAGornbein J. (1994) The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology1944;44: 2308-2314.

[36] Bozeat S, Gregory CA, Ralph MA, Hodges JR. Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer's disease? J NeurolNeurosurg Psychiatry 2000;69:178-186.

[37] Kertesz A, Davidson W,Fox H.Frontal behavioral inventory: diagnostic criteria for frontal lobe dementia. Can J Neurol Sci1997;24:29-36.

[38] Loy C T, Kril JJ, Trollor JN, et al.The case of a 48 year-old woman with bizarre and complex delusions. Nat Rev Neurol 2010;6:175-179.

[39] Liu W, Miller BL, Kramer JH.Behavioral disorders in the frontal and temporal variants of frontotemporal dementia Neurology2004;62:742-748.

[40] Diehl-Schmid J, Pohl C, Perneczky R, Forstl H,Kurz A.Behavioral disturbances in the course of frontotemporal dementia. Dement Geriatr Cogn Disord 2006;22:352-357.

[41] Srikanth S, Nagaraja AV,Ratnavalli E.Neuropsychiatric symptoms in dementia-frequency relationship to dementia severity and comparison in Alzheimer's disease vascular dementia and frontotemporal dementia. J Neurol Sci2005;236:43-48.

[42] Pasquier F, Lebert F, Lavenu I,Guillaume B.The clinical picture of frontotemporal dementia: diagnosis and follow-up. Dement Geriatr Cogn Disord1999;10( Suppl 1):10-14.

[43] Kipps CM, Nestor PJ, Fryer TD, Hodges JR. Behavioural variant frontotemporal dementia: not all it seems? Neurocase2007;13:237-247.

[44] Davies RR, Kipps CM, Mitchell J, Kril JJ, Halliday GM, Hodges JR. Progression in frontotemporal dementia: identifying a benign behavioral variant by magnetic resonance imaging. Arch Neurol2006;63: 1627-1631.

[45] Hornberger M, Shelley BP, Kipps CM, Piguet O, Hodges JR. Can progressive and non-progressive behavioral variant frontotemporal dementia be distinguished at presentation? J NeurolNeurosurg Psychiatry 2009;80:591-593.

[46] Piguet O, Hornberger M, Shelley BP, Kipps CMHodges JR.Sensitivity of current criteria for the diagnosis of behavioral variant frontotemporal dementia. Neurology2009;72:732-737.

[47] Kipps CM, Hodges JR, Fryer TD,Nestor PJ.Combined magnetic resonance imaging and positron emission tomography brain imaging in behavioural variant frontotemporal degeneration: refining the clinical phenotype. Brain2009;132:2566-2578.

[48] Khan BK, Yokoyama JS, Takada LT. Atypical slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. J NeurolNeurosurg Psychiatry 2012;83:358-364.

[49] Mioshi E, Kipps CM, Dawson K, Mitchell J, Graham A, Hodges JR. Activities of daily living in frontotemporal dementia and Alzheimer disease Neurology2007;68:2077-2084

[50] Kipps CM, Nestor PJ, Dawson CE, Mitchell J, Hodges JR.Measuring progression in frontotemporal dementia: Implications for therapeutic interventions. Neurology 2008;70:2046-2052.

[51] Giovagnoli AR, Erbetta A, Reati F,Bugiani O. Differential neuropsychological patterns of frontal variant frontotemporal dementia and Alzheimer's disease in a study of diagnostic concordance. Neuropsychologia 2008;46:1495-1504.

[52] Hornberger M, Piguet O, Kipps C, Hodges JR. Executive function in progressive and nonprogressive behavioral variant frontotemporal dementia. Neurology 2008;71:1481-1488.

[53] Gleichgerrcht E, Torralva T, Roca M,Manes F. Utility of an abbreviated version of the executive and social cognition battery in the detection of executive deficits in early behavioral variant frontotemporal dementia patients. J Int Neuropsychol Soc 2010;19:1-8.

[54] Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain2011;34:2456-2477.

[55] Graham A, Davies R, Xuereb J, et al. Pathologically proven frontotemporal dementia presenting with severe amnesia. Brain2005;128:597-605.

[56] Hornberger M,. Piguet O Episodic memory in frontotemporal dementia: a critical review. Brain2012;135:678-692.

[57] Hornberger M, Piguet O, Graham AJ, Nestor PJ, Hodges JR. How preserved is episodic memory in behavioral variant frontotemporal dementia?Neurology2010;74:472-479.

[58] Irish M, Hornberger M, Lah S, et al. Profiles of recent autobiographical memory retrieval in semantic dementia behavioural-variant frontotemporal dementia and Alzheimer's disease. Neuropsychologia2011; 49:2694-2702.

[59] Irish M, Piguet O, Hodges JR.Self-projection and the default network in frontotemporal dementia. Nat Rev Neurol 2011;8:152-161.

[60] Fellows LK, Farah MJ. Ventromedial frontal cortex mediates affective shifting in humans: evidence from a reversal learning paradigm. Brain2003;126:1830-1837.

[61] Bertoux M, Funkiewiez A, O'Callaghan C, Dubois B.. Hornberger M Sensitivity and specificity of ventromedial prefrontal cortex tests in behavioral variant frontotemporal dementia. Alzheimers Dement 2012: S1552-5260(12)02499-5.

[62] Torralva T, Roca M, Gleichgerrcht E, Bekinschtein T, Manes F. A neuropsychological battery to detect specific executive and social cognitive impairments in early frontotemporal dementia. Brain2009;132: 1299-1309.

[63] Kumfor F,. Piguet O Disturbance of emotion processing in frontotemporal dementia: a synthesis of cognitive and neuroimaging findings. Neuropsychol Rev 2012;22:280 -297.

[64] Rankin KP, Gorno-Tempini ML, Allison SC, et al. Structural anatomy of empathy in neurodegenerative disease Brain2006;129:2945-2956

[65] Rankin KP, Salazar A, Gorno-Tempini ML, et al. Detecting sarcasm from paralinguistic cues: anatomic and cognitive correlates in neurodegenerative disease. NeuroImage 2009;47:2005-2015.

[66] Snowden JS, Austin NA, Sembi S, Thompson JC, Craufurd D,Neary D. Emotion recognition in Huntington's disease and frontotemporal dementia. Neuropsychologia2008;46:2638-2649.

[67] Hsieh S, Hodges JR,. Piguet O Recognition of positive vocalizations is impaired in behavioral-variant frontotemporal dementia. J Int Neuropsychol Soc2013; 1:1-5.

[68] Hsieh S, Foxe D, Leslie F, Savage S, Piguet O, Hodges JR. Grief and joy: emotion word comprehension in the dementias. Neuropsychology 2012;26:624-630.

[69] Omar R, Henley SM, Bartlett JW, et al. The structural neuroanatomy of music emotion recognition: evidence from frontotemporal lobar degeneration. NeuroImage2011;56:1814-1821.

[70] Werner KH, Roberts NA, Rosen HJ, et al. Emotional reactivity and emotion recognition in frontotemporal lobar degeneration. Neurology 2007;69:148-155.

[71] Sturm VE, Rosen HJ, Allison S, Miller BL,Levenson RW. Self-conscious emotion deficits in frontotemporal lobar degeneration. Brain2006; 129:2508-2516.

[72] Sturm VE, Sollberger M, Seeley WW. Role of right pregenual anterior cingulate cortex in self-conscious emotional reactivity. Soc Cogn Affect Neurosci 2012 (Epub ahead of print).

[73] Kumfor F, Miller L, Lah S, et al. Are you really angry? The effect of intensity on facial emotion recognition in frontotemporal dementia. Soc Neurosci 2011; 6:502-514.

[74] Miller L A, Hsieh S, Lah S, Savage S, Hodges JR,. Piguet O One size does not fit all: Face emotion processing impairments in semantic dementia behavioural-variant frontotemporal dementia and Alzheimer's disease are mediated by distinct cognitive deficits. Behav Neurol 2012;25:53-60.

[75] Fernandez-Duque D, Hodges SD, Baird JA, Black SE. Empathy in frontotemporal dementia and Alzheimer's disease. J Clin Exp Neuropsychol 2010;32:289-298.

[76] Gregory C, Lough S, Stone V, et al. Theory of mind in patients with frontal variant frontotemporal dementia and Alzheimer's disease: theoretical and practical implications. Brain2002;125:752-764.

[77] Lough S, Kipps CM, Treise C, Watson P, Blair JR, Hodges JR.Social reasoning emotion and empathy in frontotemporal dementia Neuropsychologia2006;44:950-958.

[78] Shany-Ur T, Poorzand P, Grossman SN. Comprehension of insincere communication in neurodegenerative disease: lies sarcasm and theory of mind. Cortex 2012;48:1329-1341.

[79] Mendez MF, Shapira JS. Altered emotional morality in frontotemporal dementia. Cogn Neuropsychiatry 2009;14:165-179.

[80] Ibanez A, Manes F.Contextual social cognition and the behavioral variant of frontotemporal dementia. Neurology 2012;78:1354-1362.

[81] Kipps CM, Nestor PJ, Acosta-Cabronero J, Arnold R, Hodges JR. Understanding social dysfunction in the behavioural variant of frontotemporal dementia: the role of emotion and sarcasm processing. Brain2009;132:592-603.

[82] McDonald S, Flanagan S, Rollins J,Kinch J.TASIT: A new clinical tool for assessing social perception after traumatic brain injury. J Head Trauma Rehabil 2003;18:219-238.

[83] Davatzikos C, Resnick SM, Wu X, Parmpi P, Clark CM. Individual patient diagnosis of AD and FTD via high-dimensional pattern classification of MRI. NeuroImage2008;41:1220-1227.

[84] Hornberger M, Savage S, Hsieh S, Mioshi E, Piguet O, Hodges JR.Orbitofrontal dysfunction discriminates behavioral variant frontotemporal dementia from Alzheimer's disease. Dementia and Geriatric Cognitive Disorders 2010;30:547-552.

[85] Seeley WW, Crawford R, Rascovsky K,et al. Frontal paralimbic network atrophy in very mild behavioral variant frontotemporal dementia. Arch Neurol2008;65:249-255.

[86] Boccardi M, Sabattoli F, Laakso MP, et al. Frontotemporal dementia as a neural system disease. Neurobiol Aging 2005;26:37-44.

[87] Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseases target large-scale human brain networks. Neuron2009;62:42-52.

[88] Seeley WW, Carlin DA, Allman JM, et al. Early frontotemporal dementia targets neurons unique to apes and humans. Ann Neurol2006;60: 660-667.

[89] Zhou J, Greicius MD, Gennatas ED, et al. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease. Brain2010;133:1352-1367.

[90] Josephs KA, Whitwell JL, Parisi JE et al. Caudate atrophy on RI is a characteristic feature of FTLD-FUS. Eur J Neurol2010;17:969-975.

[91] Whitwell JL, Josephs KA, Rossor MN, et al. Magnetic resonance imaging signatures of tissue pathology in frontotemporal dementia. Arch Neurol2005;62:1402-1408.

[92] Pereira JM, Williams GB, Acosta-Cabronero J, et al. Atrophy patterns in histologic vs clinical groupings of frontotemporal lobar degeneration. Neurology 2009;72:1653-1660.

[93] Barnes J, Whitwell JL, Frost C, Josephs KA, Rossor M, Fox NC. Measurements of the amygdala and hippocampus in pathologically confirmed Alzheimer disease and frontotemporal lobar degeneration. Arch Neurol2006;63:1434-1439.

[94] Piguet O, Petersen A, Yin Ka Lam B, et al. MEating and hypothalamus changes in behavioral-variant frontotemporal dementia. Ann Neurol2011;69:312-319.

[95] Filippi M, Agosta F, Scola E, et al. Functional network connectivity in the behavioral variant of frontotemporal dementia. Cortex2012:S0010-9452(12)00303-6.

[96] Agosta F, Scola E, Canu E, et al. White matter damage in frontotemporal lobar degeneration spectrum. Cereb Cortex2012;22:2705-2714.

[97] Chao LL, Schuff N, Clevenger EM, et al. Patterns of white matter atrophy in frontotemporal lobar degeneration. Arch Neurol2007;64:1619-1624.

[98] Zhang Y, Tartaglia MC, Schuff N, et al. MRI signatures of brain macrostructural atrophy and microstructural degradation in frontotemporal lobar degeneration subtypes. J Alzheimers Dis2013;33:431-444.

[99] Zhang Y, Schuff N, Du AT. White matter damage in frontotemporal dementia and Alzheimer's disease measured by diffusion MRI. Brain2009;132:2579-2592.

[100] WhitwellJL, AvulaR, Senjem ML, et al. Gray and white matter water diffusion in the syndromic variants of frontotemporal dementia. Neurology 2010;74:1279-1287.

[101] Varma AR, Adams W, Lloyd JJ et al. Diagnostic patterns of regional atrophy on MRI and regional cerebral blood flow change on SPECT in young onset patients with Alzheimer's disease frontotemporal dementia and vascular dementia. Acta Neurol Scand 2002;105:261-269.

[102] Kanda T, Ishii K, Uemura T, Miyamoto N, et al. Comparison of grey matter and metabolic reductions in frontotemporal dementia using FDG-PET and voxel-based morphometric MR studies. Eur J Nucl Med Mol Imaging2008;35:2227-2234.

[103] Engler H, Santillo AF, Wang SX, et al. In vivo amyloid imaging with PET in frontotemporal dementia. Eur J Nucl Med Mol Imaging2008;35:100-106.

[104] Rowe CC, Ng S, Ackermann U, et al. Imaging beta-amyloid burden in aging and dementia. Neurology 2007;68:1718-1725.

[105] Boxer AL, Boeve BF. Frontotemporal dementia treatment: current symptomatic therapies and implications of recent genetic biochemical and neuroimaging studies. Alzheimer Dis Assoc Disord 2007;21:S79-87.

[106] Deakin JB, Rahman S, Nestor PJ, Hodges JR, Sahakian BJ. Paroxetine does not improve symptoms and impairs cognition in frontotemporal dementia: a double-blind randomized controlled trial. Psychopharmacology (Berl) 2004;172:400-408.

[107] 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 Neurol2003;49:13-19.

[108] 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 DisOther Demen 2003;18:205-214.

[109] Moretti R, Torre P, Antonello RM, Cattaruzza T, Cazzato G, Bava A.Rivastigmine in frontotemporal dementia: an open-label study. Drugs Aging 2004;21:931-937.

[110] Mendez MF, Shapira JS, McMurtray A, Licht E. Preliminary findings: behavioral worsening on donepezil in patients with frontotemporal dementia. Am J Geriatr Psychiatry 2007;15:84-87.

[111] Boxer AL, Knopman DS, Kaufer DI, et al. Memantine in patients with frontotemporal lobar degeneration: a multicentre randomised double-blind placebo-controlled trial. Lancet Neurol2013;12:149-156.

[112] Vercelletto M, Boutoleau-Bretonniere C, Volteau C, Puel M, Auriacombe S, Sarazin M. French research network on Frontotemporal dementiaMemantine in behavioral variant frontotemporal dementia: negative results. J Alzheimers Dis2011;23:749-759.

[113] Mendez MF. Frontotemporal dementia: therapeutic interventions. Front Neurol Neurosci 2009;24:168-178.

[114] Merrilees J, Klapper J, Murphy J, Lomen-Hoerth C, Miller BL. Cognitive and behavioral challenges in caring for patients with frontotemporal dementia and amyotrophic lateral sclerosis . Amyotroph Lateral Scler 2010;11:298-302.

[115] Mioshi E, McKinnon C, Savage S, O'Connor CM, Hodges JR.Improving Burden and Coping Skills in Frontotemporal Dementia Caregivers: A Pilot Study. Alzheimer Dis Assoc Disord2012 (Epub ahead of print).

[116] Boutoleau-Bretonniere C, Vercelletto M, Volteau C, Renou P, Lamy E. Zarit burden inventory and activities of daily living in the behavioral variant of frontotemporal dementia. Dement Geriatr Cogn Disord2008; 25:272-277.

[117] Mioshi E, Bristow M, Cook R, Hodges JR. Factors underlying caregiver stress in frontotemporal dementia and Alzheimer's disease. Dement Geriatr Cogn Disord2009;27:76-81.

[118] Riedijk SR, De Vugt ME, Duivenvoorden HJ, et al. Caregiver burden health-related quality of life and coping in dementia caregivers: a comparison of frontotemporal dementia and Alzheimer's disease. Dement Geriatr Cogn Disord2006;22:405-412.

[119] Miller L A, Mioshi E, Savage S, Lah S, Hodges JR,. Piguet O Identifying cognitive and demographic variables that contribute to carer urden in dementia. Dem Ger Cogn Disord 2013 (In press)

[120] Mioshi E, Foxe D, Leslie F, Savage S, et al. The Impact of Dementia Severity on Caregiver Burden in Frontotemporal Dementia and Alzheimer Disease. Alzheimer Dis Assoc Disord2013 (In Press).

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