Comment
Frontotemporal dementia: a peek under its invisibility cloak Published Online February 4, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)70019-0 See Articles page 253
236
Frontotemporal dementia is a group of neurodegenerative diseases1 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.2 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.3 The first genetic mutation causing frontotemporal dementia was reported more than a decade ago.4 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 dementia5 and have differing clinical,6 neuroanatomical,7 and neuropathological associations.8 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.9 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 colleagues10 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 crosssectional 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 www.thelancet.com/neurology Vol 14 March 2015
Comment
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”.11
5 6
7
Keith A Josephs Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA [email protected]
8
I declare no competing interests. My research is supported by the National Institutes of Health and the Alzheimer’s Association.
9
Copyright © Josephs. Open Access article distributed under the terms of CC BY-NC-ND.
10
1 2 3
4
Josephs KA. Frontotemporal dementia and related disorders: deciphering the enigma. Ann Neurol 2008; 64: 4–14. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51: 1546–54. Hu WT, Seelaar H, Josephs KA, et al. Survival profiles of patients with frontotemporal dementia and motor neuron disease. Arch Neurol 2009; 66: 1359–64. 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: 702–05.
11
van der Zee J, Van Broeckhoven C. Dementia in 2013: frontotemporal lobar degeneration-building on breakthroughs. Nat Rev Neurol 2014; 10: 70–72. Mahoney CJ, Beck J, Rohrer JD, et al. Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain 2012; 135: 736–50. Whitwell JL, Weigand SD, Boeve BF, et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 2012; 135: 794–806. Sieben A, Van Langenhove T, Engelborghs S, et al. The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathol 2012; 124: 353–72. Rosen HJ, Gorno-Tempini ML, Goldman WP, et al. Patterns of brain atrophy in frontotemporal dementia and semantic dementia. Neurology 2002; 58: 198–208. Rohrer 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)70324-2. National Churchill Museum. Winston Churchill and the Cold War. http://www. nationalchurchillmuseum.org/winston-churchill-and-the-cold-war.html (accessed Jan 29, 2015).
Substantial advances in multiple sclerosis research have occurred in recent years, from the advent of oral therapies for relapsing-remitting multiple sclerosis1 to the discovery of previously unknown genetic risk variants.2 Nevertheless, the cause or causes of multiple sclerosis continue to elude us. Susceptibility probably involves a combination of common genetic inheritance and environmental exposures, but the specific elements remain unclear. Worldwide, as populations age, the prevalence of multiple sclerosis has also increased,3 inflicting immense costs, both personal and societal. There is an urgent need to get to the root of the problem, to develop effective strategies aimed at prevention. These lofty goals cannot be achieved without a methodical assessment of the best available evidence as to what might cause multiple sclerosis, particularly those factors that are amenable to change. Belbasis and colleagues’ umbrella review in The Lancet Neurology4 represents decades of research into the environmental risk factors for multiple sclerosis, providing a rigorous and systematic assessment of published reviews and meta-analyses. Although not a new concept, an umbrella review has not been done in multiple sclerosis before; previous systematic reviews have typically focused on a single risk factor, making this mega-meta-analysis unique. Of the 20 reviews included, 17 contained 44 unique meta-analyses, with medians of 933 patients with www.thelancet.com/neurology Vol 14 March 2015
multiple sclerosis and eight original studies per metaanalysis.4 About half of the meta-analyses were related to vaccines or infections. Two environmental exposures showed credible evidence of a relation with multiple sclerosis: smoking and Epstein-Barr virus (the latter measured as IgG seropositivity for Epstein-Barr virus nuclear antigen or history of infectious mononucleosis). All three factors showed a consistent and significant association with multiple sclerosis, without suggestion of bias or large statistical heterogeneity (ie, the variability between the original study results was judged to be acceptable). What does this mean for potential public health strategies to prevent multiple sclerosis? Both the Epstein-Barr virus risk factors had reasonable summary effect sizes, with odds ratios greater than 2. However, more than 90% of the world’s population is positive for Epstein-Barr virus,5 and the possibility of developing a safe vaccine against a virus human beings have co-existed with for millennia is uncertain.6 Smoking appears more amenable to modification, but the effect size was also more modest (odds ratio=1·52, 95% CI 1·39–1·66) and smoking is already a target of many governmental health strategies.7 Nonetheless, counselling for family members or other individuals at higher than average risk of developing multiple sclerosis seems a pragmatic option.
Science Photo Library
The systematic search for risk factors in multiple sclerosis
Published Online February 4, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)70015-3 See Articles page 263
237
Frontotemporal dementia: a peek under its invisibility cloak Published Online February 4, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)70019-0 See Articles page 253
236
Frontotemporal dementia is a group of neurodegenerative diseases1 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.2 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.3 The first genetic mutation causing frontotemporal dementia was reported more than a decade ago.4 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 dementia5 and have differing clinical,6 neuroanatomical,7 and neuropathological associations.8 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.9 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 colleagues10 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 crosssectional 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 www.thelancet.com/neurology Vol 14 March 2015
Comment
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”.11
5 6
7
Keith A Josephs Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA [email protected]
8
I declare no competing interests. My research is supported by the National Institutes of Health and the Alzheimer’s Association.
9
Copyright © Josephs. Open Access article distributed under the terms of CC BY-NC-ND.
10
1 2 3
4
Josephs KA. Frontotemporal dementia and related disorders: deciphering the enigma. Ann Neurol 2008; 64: 4–14. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51: 1546–54. Hu WT, Seelaar H, Josephs KA, et al. Survival profiles of patients with frontotemporal dementia and motor neuron disease. Arch Neurol 2009; 66: 1359–64. 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: 702–05.
11
van der Zee J, Van Broeckhoven C. Dementia in 2013: frontotemporal lobar degeneration-building on breakthroughs. Nat Rev Neurol 2014; 10: 70–72. Mahoney CJ, Beck J, Rohrer JD, et al. Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain 2012; 135: 736–50. Whitwell JL, Weigand SD, Boeve BF, et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 2012; 135: 794–806. Sieben A, Van Langenhove T, Engelborghs S, et al. The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathol 2012; 124: 353–72. Rosen HJ, Gorno-Tempini ML, Goldman WP, et al. Patterns of brain atrophy in frontotemporal dementia and semantic dementia. Neurology 2002; 58: 198–208. Rohrer 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)70324-2. National Churchill Museum. Winston Churchill and the Cold War. http://www. nationalchurchillmuseum.org/winston-churchill-and-the-cold-war.html (accessed Jan 29, 2015).
Substantial advances in multiple sclerosis research have occurred in recent years, from the advent of oral therapies for relapsing-remitting multiple sclerosis1 to the discovery of previously unknown genetic risk variants.2 Nevertheless, the cause or causes of multiple sclerosis continue to elude us. Susceptibility probably involves a combination of common genetic inheritance and environmental exposures, but the specific elements remain unclear. Worldwide, as populations age, the prevalence of multiple sclerosis has also increased,3 inflicting immense costs, both personal and societal. There is an urgent need to get to the root of the problem, to develop effective strategies aimed at prevention. These lofty goals cannot be achieved without a methodical assessment of the best available evidence as to what might cause multiple sclerosis, particularly those factors that are amenable to change. Belbasis and colleagues’ umbrella review in The Lancet Neurology4 represents decades of research into the environmental risk factors for multiple sclerosis, providing a rigorous and systematic assessment of published reviews and meta-analyses. Although not a new concept, an umbrella review has not been done in multiple sclerosis before; previous systematic reviews have typically focused on a single risk factor, making this mega-meta-analysis unique. Of the 20 reviews included, 17 contained 44 unique meta-analyses, with medians of 933 patients with www.thelancet.com/neurology Vol 14 March 2015
multiple sclerosis and eight original studies per metaanalysis.4 About half of the meta-analyses were related to vaccines or infections. Two environmental exposures showed credible evidence of a relation with multiple sclerosis: smoking and Epstein-Barr virus (the latter measured as IgG seropositivity for Epstein-Barr virus nuclear antigen or history of infectious mononucleosis). All three factors showed a consistent and significant association with multiple sclerosis, without suggestion of bias or large statistical heterogeneity (ie, the variability between the original study results was judged to be acceptable). What does this mean for potential public health strategies to prevent multiple sclerosis? Both the Epstein-Barr virus risk factors had reasonable summary effect sizes, with odds ratios greater than 2. However, more than 90% of the world’s population is positive for Epstein-Barr virus,5 and the possibility of developing a safe vaccine against a virus human beings have co-existed with for millennia is uncertain.6 Smoking appears more amenable to modification, but the effect size was also more modest (odds ratio=1·52, 95% CI 1·39–1·66) and smoking is already a target of many governmental health strategies.7 Nonetheless, counselling for family members or other individuals at higher than average risk of developing multiple sclerosis seems a pragmatic option.
Science Photo Library
The systematic search for risk factors in multiple sclerosis
Published Online February 4, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)70015-3 See Articles page 263
237
