FTLD Explained.  FTLD occurs when certain regions of the brain including those involved in executive function - critical thinking, problem solving and complex decision-making - shrink (red) due to neuronal loss.  FTLD is also known as frontotemporal dementia (FTD).  Here, an MRI of a person with a form of FTLD similar to ALS-FTLD is shown. Adapted from Whitwell, J.L. and Josephs, K.A. (2012). Courtesy of Nature Publishing Group. All Rights Reserved.

Neurologists may need to keep an eye out for cognitive and behavioral changes in people showing signs of ALS, according to a new study. 

The research team, led by Trinity College Dublin neurologist Orla Hardiman MD FRCP, found that 50% of people examined with the most common form of familial ALS identified to date also showed signs of frontotemporal lobar degeneration (FTLD).  The brain disorder might result in difficulties in critical thinking, problem solving and making complex decisions.

The study, which included 20 people with familial ALS harboring repeat expansions in the C9ORF72 gene, is the first to clinically describe this form of ALS.

The results are published in the March issue of Lancet Neurology.

Scientists first suspected that ALS might fall on the same clinical spectrum as FTLD in 2000 when a research team led by Massachusetts General Hospital neurologist Robert Brown MD PhD identified families with a history of both diseases. Just last fall, two independent research teams discovered one such cause of this so-called ALS with FTLD: repeat expansions in the gene, C9ORF72. 

Now, researchers report that people harboring repeat expansions in the C9ORF72 gene might have a distinct subtype of ALS. The C9ORF72-linked form of ALS appears to be earlier onset, about twice as rapidly progressing and may result in certain cognitive and behavioral changes including increased indifference and difficulties in problem solving and making complex decisions.  The disease appears to be distinguished from other forms of ALS using advanced magnetic resonance imaging (MRI)

The study is one of three studies this month that confirms that repeat expansions in the C9ORF72 gene are the most common cause of inherited forms of ALS, ALS-FTLD and FTLD.

To test or not to test

Most people with C9ORF72-linked ALS identified by the team had a strong history of neurodegenerative disease.  But researchers caution that larger studies are needed to determine whether or not genetic testing is warranted - especially for family members of patients without any signs of either ALS or FTLD. The penetrance is variable.  Nearly one out of every three people with repeat expansions in the C9ORF72 gene (6 out of 20) lived into their 80s and 90s and showed no signs of the disease.  What’s more, researchers remain unsure how many of these repeat sequences in the C9ORF72 gene are needed to trigger the disease.

To further explore the role of the brain in ALS, check out MRI, Make that a double.  To learn more about the emerging role of C9ORF72 in ALS, read Silence is not golden


Byrne, S. et al. (2012) Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study.  Lancet Neurology 11(3), 232-240. Abstract | Full Text (Subscription Required)

DeJesus-Hernandez, M. et al. (2011) Expanded GGGGCC hexanucleotide repeat in a noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS Neuron 72(2), 245-256. Abstract | Full Text (Subscription Required)

Renton, A.E. et al. (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72(2), 257-268. Abstract | Full Text (Subscription Required)

Hsiung, G.Y. et al. (2012) Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain doi: 10.1093/brain/awr354. Abstract | Full Text (Subscription Required)

Simón-Sánchez J, et al. (2012) The clinical and pathological phenotype of C9orf72 hexanucleotide repeat expansions. Brain doi: 10.1093/brain/awr353. Abstract | Full Text  (Subscription Required)

Whitwell, J.L. & Josephs, K.A. (2012)  Neuroimaging in frontotemporal lobar degeneration—predicting molecular pathology Nature Reviews Neurology doi:10.1038/nrneurol.2012.7.  Abstract | Full Text (Subscription Required)

Further Reading

Andersen, P.M. (2012) Mutation in C9orf72 changes the boundaries of ALS and FTD.  Lancet Neurology 11(3), 205-207.  Full Text (Subscription Required)

Phukan, J., Elamin, M., Bede, P., Jordan, N., Gallagher, L., Byrne, S., Lynch, C., Pender, N. and Hardiman, O. (2012) The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. Journal of Neurology, Neurosurgery and Psychiatry 83, 102-108. Abstract | Full Text (Subscription Required)

Learn more about cognitive and behavioral changes in people with ALS