Frontotemporal dementia: a peek under its invisibility cloak
Authors: Keith A Josephs
Journal: The Lancet Neurology (2015)

Frontotemporal dementia is a group of neurodegenerative diseases1Josephs KA Frontotemporal dementia and related disorders: deciphering the enigma.Ann Neurol. 2008; 64: 4-14Crossref PubMed Scopus (139) Google Scholar that eat away at our core being. Like its comrade, Alzheimer's disease, ageing is its best friend. Patients and families tell tales of behavioural changes that sometimes encroach on the incredible: “Mummy threw her faeces at me this morning, doc”. Language can also be lost.2Neary D Snowden JS Gustafson L et al.Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria.Neurology. 1998; 51: 1546-1554Crossref PubMed Scopus (4402) Google Scholar Words like “dog”, “eyes”, and “thing” are retained, whereas words like “equestrian”, “aardvark”, and “asparagus” are meaningless. With progression, eventually only the shell of a person lingers on, until death ensues. This disease not only steals individual lives, but also can target families. In some instances, family members can be afflicted with motor neuron disease, which can be even more devastating than frontotemporal dementia.3Hu WT Seelaar H Josephs KA et al.Survival profiles of patients with frontotemporal dementia and motor neuron disease.Arch Neurol. 2009; 66: 1359-1364Crossref PubMed Scopus (77) Google Scholar The first genetic mutation causing frontotemporal dementia was reported more than a decade ago.4Hutton 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: 702-705Crossref PubMed Scopus (2877) Google Scholar Three major genetic abnormalities are now recognised: mutations in the microtubule-associated protein tau and the progranulin genes, and repeat expansions in the C9orf72 gene. Mutations in these three genes account for most genetic abnormalities identified in frontotemporal dementia5van der Zee J Van Broeckhoven C Dementia in 2013: frontotemporal lobar degeneration-building on breakthroughs.Nat Rev Neurol. 2014; 10: 70-72Crossref PubMed Scopus (18) Google Scholar and have differing clinical,6Mahoney CJ Beck J Rohrer JD et al.Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features.Brain. 2012; 135: 736-750Crossref PubMed Scopus (336) Google Scholar neuroanatomical,7Whitwell JL Weigand SD Boeve BF et al.Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics.Brain. 2012; 135: 794-806Crossref PubMed Scopus (306) Google Scholar and neuropathological associations.8Sieben A Van Langenhove T Engelborghs S et al.The genetics and neuropathology of frontotemporal lobar degeneration.Acta Neuropathol. 2012; 124: 353-372Crossref PubMed Scopus (192) Google ScholarLike all neurodegenerative disease, by the time the patient becomes affected, irreversible changes are likely to have already been set in motion. Atrophy can already be detected, predominantly in the frontal and temporal lobes.9Rosen HJ Gorno-Tempini ML Goldman WP et al.Patterns of brain atrophy in frontotemporal dementia and semantic dementia.Neurology. 2002; 58: 198-208Crossref PubMed Scopus (721) Google Scholar By then, it is probably too late. Unfortunately, most published studies in frontotemporal dementia investigate patients who are already symptomatic. The missing piece is the presymptomatic stage, when symptoms, and even signs, are essentially invisible. Understanding this presymptomatic stage is crucial if therapeutic measures are to be helpful to patients with the disease. The dilemma is how to identify such patients. One solution is to study affected families in which genetic status is known. Such studies provide three classes of participants: those without a mutation; those with a mutation who are symptomatic; and those with a mutation who are presymptomatic.In The Lancet Neurology, Rohrer and colleagues10Rohrer JD Nicholas JM Cash DM et al.Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis.Lancet Neurology. 2015; (published online Feb 4.)http://dx.doi.org/10.1016/S1474-4422(14)70324-2PubMed Google Scholar capitalise on the value of familial studies to peek under the cloak of invisibility of the presymptomatic stage of frontotemporal dementia. The investigators, from the UK, Europe, and Canada, pooled and analysed clinical, neuropsychological, and neuroimaging data from 220 genetically characterised participants: 118 carriers of mutations associated with frontotemporal dementia and 102 non-carriers who were relatives of symptomatic carriers. With an interesting approach to analysis, the investigators used mixed-effects models to estimate the earliest points in time that clinical or neuroimaging abnormalities could be identified. One of the key findings of the study was the identification of regional neuroimaging changes on MRI as much as a decade before predicted age of onset. Not surprisingly, neuroimaging abnormalities predated neuropsychological deficits by 5 years. The major strength of this study, other than assessment of presymptomatic patients, is its multicentre design, which produced large numbers of participants to be analysed, including 78 people who were asymptomatic at the time of assessment. These large numbers allowed for elaborate statistical analysis and provided power to detect subtle abnormalities. Some people will certainly quibble about the methods used for estimation of expected symptoms onset—calculation of average onset for each family on the basis of affected family members—but unless a better approach can be proposed, this method is as good as it can be with use of cross-sectional data for longitudinal prediction.One of the main impetuses for this study is the search for the holy grail of neurodegenerative diseases—biomarkers. Although neuroimaging biomarkers seem, impressively, to be able to detect change a decade before disease onset in this study, genetic testing will always be king of the biomarker arena. However, this fact should not downplay the importance of neuroimaging. Neuroimaging biomarkers enable change to be measured over time, which is one of the important attributes of outcome measures used in therapeutic trials; to show a reduction in progression is typically necessary to prove pharmacological efficacy. Therefore, if we are to stamp out frontotemporal dementia, a biomarker that can detect change in the presymptomatic stage of disease is not only useful, but essential. As these presymptomatic individuals are studied over time, the investigators should be able to provide us with longitudinal data to validate their cross-sectional predictions. The discipline of frontotemporal dementia has been fast moving with many advances over the past few years and these findings represent a further step in the right direction, although the ultimate prize of a cure remains elusive. As Winston Churchill said, “It is always wise to look ahead, but difficult to look further than you can see”.11National Churchill MuseumWinston Churchill and the Cold War.http://www.nationalchurchillmuseum.org/winston-churchill-and-the-cold-war.htmlGoogle ScholarI declare no competing interests. My research is supported by the National Institutes of Health and the Alzheimer's Association. Frontotemporal dementia is a group of neurodegenerative diseases1Josephs KA Frontotemporal dementia and related disorders: deciphering the enigma.Ann Neurol. 2008; 64: 4-14Crossref PubMed Scopus (139) Google Scholar that eat away at our core being. Like its comrade, Alzheimer's disease, ageing is its best friend. Patients and families tell tales of behavioural changes that sometimes encroach on the incredible: “Mummy threw her faeces at me this morning, doc”. Language can also be lost.2Neary D Snowden JS Gustafson L et al.Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria.Neurology. 1998; 51: 1546-1554Crossref PubMed Scopus (4402) Google Scholar Words like “dog”, “eyes”, and “thing” are retained, whereas words like “equestrian”, “aardvark”, and “asparagus” are meaningless. With progression, eventually only the shell of a person lingers on, until death ensues. This disease not only steals individual lives, but also can target families. In some instances, family members can be afflicted with motor neuron disease, which can be even more devastating than frontotemporal dementia.3Hu WT Seelaar H Josephs KA et al.Survival profiles of patients with frontotemporal dementia and motor neuron disease.Arch Neurol. 2009; 66: 1359-1364Crossref PubMed Scopus (77) Google Scholar The first genetic mutation causing frontotemporal dementia was reported more than a decade ago.4Hutton 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: 702-705Crossref PubMed Scopus (2877) Google Scholar Three major genetic abnormalities are now recognised: mutations in the microtubule-associated protein tau and the progranulin genes, and repeat expansions in the C9orf72 gene. Mutations in these three genes account for most genetic abnormalities identified in frontotemporal dementia5van der Zee J Van Broeckhoven C Dementia in 2013: frontotemporal lobar degeneration-building on breakthroughs.Nat Rev Neurol. 2014; 10: 70-72Crossref PubMed Scopus (18) Google Scholar and have differing clinical,6Mahoney CJ Beck J Rohrer JD et al.Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features.Brain. 2012; 135: 736-750Crossref PubMed Scopus (336) Google Scholar neuroanatomical,7Whitwell JL Weigand SD Boeve BF et al.Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics.Brain. 2012; 135: 794-806Crossref PubMed Scopus (306) Google Scholar and neuropathological associations.8Sieben A Van Langenhove T Engelborghs S et al.The genetics and neuropathology of frontotemporal lobar degeneration.Acta Neuropathol. 2012; 124: 353-372Crossref PubMed Scopus (192) Google Scholar Like all neurodegenerative disease, by the time the patient becomes affected, irreversible changes are likely to have already been set in motion. Atrophy can already be detected, predominantly in the frontal and temporal lobes.9Rosen HJ Gorno-Tempini ML Goldman WP et al.Patterns of brain atrophy in frontotemporal dementia and semantic dementia.Neurology. 2002; 58: 198-208Crossref PubMed Scopus (721) Google Scholar By then, it is probably too late. Unfortunately, most published studies in frontotemporal dementia investigate patients who are already symptomatic. The missing piece is the presymptomatic stage, when symptoms, and even signs, are essentially invisible. Understanding this presymptomatic stage is crucial if therapeutic measures are to be helpful to patients with the disease. The dilemma is how to identify such patients. One solution is to study affected families in which genetic status is known. Such studies provide three classes of participants: those without a mutation; those with a mutation who are symptomatic; and those with a mutation who are presymptomatic. In The Lancet Neurology, Rohrer and colleagues10Rohrer JD Nicholas JM Cash DM et al.Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis.Lancet Neurology. 2015; (published online Feb 4.)http://dx.doi.org/10.1016/S1474-4422(14)70324-2PubMed Google Scholar capitalise on the value of familial studies to peek under the cloak of invisibility of the presymptomatic stage of frontotemporal dementia. The investigators, from the UK, Europe, and Canada, pooled and analysed clinical, neuropsychological, and neuroimaging data from 220 genetically characterised participants: 118 carriers of mutations associated with frontotemporal dementia and 102 non-carriers who were relatives of symptomatic carriers. With an interesting approach to analysis, the investigators used mixed-effects models to estimate the earliest points in time that clinical or neuroimaging abnormalities could be identified. One of the key findings of the study was the identification of regional neuroimaging changes on MRI as much as a decade before predicted age of onset. Not surprisingly, neuroimaging abnormalities predated neuropsychological deficits by 5 years. The major strength of this study, other than assessment of presymptomatic patients, is its multicentre design, which produced large numbers of participants to be analysed, including 78 people who were asymptomatic at the time of assessment. These large numbers allowed for elaborate statistical analysis and provided power to detect subtle abnormalities. Some people will certainly quibble about the methods used for estimation of expected symptoms onset—calculation of average onset for each family on the basis of affected family members—but unless a better approach can be proposed, this method is as good as it can be with use of cross-sectional data for longitudinal prediction. One of the main impetuses for this study is the search for the holy grail of neurodegenerative diseases—biomarkers. Although neuroimaging biomarkers seem, impressively, to be able to detect change a decade before disease onset in this study, genetic testing will always be king of the biomarker arena. However, this fact should not downplay the importance of neuroimaging. Neuroimaging biomarkers enable change to be measured over time, which is one of the important attributes of outcome measures used in therapeutic trials; to show a reduction in progression is typically necessary to prove pharmacological efficacy. Therefore, if we are to stamp out frontotemporal dementia, a biomarker that can detect change in the presymptomatic stage of disease is not only useful, but essential. As these presymptomatic individuals are studied over time, the investigators should be able to provide us with longitudinal data to validate their cross-sectional predictions. The discipline of frontotemporal dementia has been fast moving with many advances over the past few years and these findings represent a further step in the right direction, although the ultimate prize of a cure remains elusive. As Winston Churchill said, “It is always wise to look ahead, but difficult to look further than you can see”.11National Churchill MuseumWinston Churchill and the Cold War.http://www.nationalchurchillmuseum.org/winston-churchill-and-the-cold-war.htmlGoogle Scholar I declare no competing interests. My research is supported by the National Institutes of Health and the Alzheimer's Association. Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysisStructural imaging and cognitive changes can be identified 5–10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials. Full-Text PDF Open Access