Long before outward signs of neurodegenerative disease, carriers of a hexanucleotide expansion in the C9ORF72 gene already have changes in their brains, according to new research. In the December 2 JAMA Neurology, researchers led by Isabelle Le Ber at the Centre de Référence des Démences Rares ou Précoces in Paris reported that asymptomatic carriers slipped up on certain cognitive tests, had diffuse cortical atrophy, thalamic shrinkage, and damage to white-matter tracts, all while still in their 30s. The expansions are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Longitudinal data will be needed to understand which of these early changes might correlate with ALS or FTD, but the findings imply that the disease process starts decades before clinical onset.

  • In C9ORF72 expansion carriers, some cortical regions are smaller and white matter tracts altered even before age 40.
  • Asymptomatic carriers scored lower than non-carriers on cognitive tests.
  • Regional atrophy and cognitive deficits did not correlate.

Repeats of the GGGGCCC sequence in C9ORF72 lead to inclusions containing expanded RNAs, as well as aggregates chock-full of the polydipeptide repeats they encode. How and when the expansions trigger neuronal demise in ALS/FTD is unclear. Pathological changes likely begin many years before the clinical manifestation of the disease, and scientists believe this preclinical period represents the optimal time to intervene with experimental therapies.

Previously, a handful of studies detected atrophy in certain regions of the brain during this preclinical period (Nov 2014 conference newsRohrer et al., 2015Walhout et al., 2015; Lee et al., 2017; Papma et al., 2017; Cash et al., 2017). However, most studied fewer than 20 asymptomatic C9 carriers. For the current study, first author Anne Bertrand and colleagues compared cognitive scores, magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI) among 41 C9 carriers and 39 noncarriers who were enrolled in PREV-DEMALS. This prospective observational study includes C9 carriers and first-degree relatives from 48 families in France. Only cross-sectional, baseline data have been analyzed so far.

In terms of cognition, C9 carriers scored slightly yet significantly lower on a praxis test, which assesses how quickly and correctly a person can turn thought into physical action. In this case, C9 carriers had difficulty performing nontransitive gestures on verbal command. Nontransitive gestures are symbolic ones, such as waving goodbye, as opposed to transitive movements—like banging a hammer. Even carriers younger than 40 years old performed slightly worse than noncarriers did on the praxis test. Bertrand was surprised by this, since praxis deficits are not one of the main features of FTD. In ALS, problems with motor function affect praxis scores, but all these participants tested normal for motor function. The findings suggest that either apraxia is an early yet non-progressing feature of disease, or perhaps that it reflects developmental, rather than neurodegenerative, effects of the C9 expansion, she said. It is also possible that praxis symptoms are common in FTD patients, but go unnoticed because some studies do not test for them, she added.

On a group level, C9 carriers also faltered on a total-recall test. Average scores were significantly lower than those of noncarriers. However, the researchers questioned the meaningfulness of this difference since scores in both groups largely overlapped.

The researchers also hunted for neuroanatomical differences in the C9 carriers. MRI data suggested smaller volumes across many regions of the cortex in C9 carriers. After correcting for multiple comparisons, C9 carriers had significantly reduced volumes in eight cortical regions. Four—a section of the right frontal cortex, left and right precuneus, and left supramarginal cortex— were also smaller in carriers younger than 40. Among subcortical regions, the right thalamus was significantly smaller in C9 carriers, again including those younger than 40. This aligns with what smaller studies have described in asymptomatic carriers, as well as with the thalamic atrophy observed in symptomatic carriers (Agosta et al., 2017). Oddly, the frontobasal cortex and primary motor cortex—prime targets of neurodegeneration in FTD and ALS, respectively—looked normal.

Cortical Shrinkage? Eight cortical regions were smaller in C9 carriers. Color scale represents significance of divergence from noncarriers. [Courtesy of Bertrand et al., JAMA Neurology, 2017.]

Diffusion tensor imaging results revealed loss of integrity of white-matter tracts that connect different regions of the brain. These changes predominated in frontal regions and affected corticospinal tracts, which are known to falter in people with FTD and ALS. After correction for multiple comparisons, eight tracts remained significantly altered: the left corticospinal tract, the right anterior thalamic radiation, four tracts connected to the frontal lobes, and two connected to the temporal lobes. Of these, the right anterior thalamic radiation and right forceps minor (in the frontal lobe) were significantly compromised in C9 carriers younger than 40. As opposed to the cortical atrophy, white-matter changes occurred in areas of the frontal cortex and corticospinal tracts that are known to degenerate during disease. The researchers therefore proposed that these white-matter alterations could predict future cognitive and motor deficits more accurately than cortical atrophy.

Troubled Tracts.

Integrity of several white-matter tracts weakened in C9 carriers. Color scale represents significance of divergence from noncarriers. [Courtesy of Bertrand et al., JAMA Neurology, 2017.]

Did any of these neuroanatomical changes correlate with cognitive ones? The researchers found that neither atrophy nor white-matter alterations correlated with praxis or recall deficits. However, they noticed that in C9 carriers the left supramarginal cortex, a region involved in the execution of nontransitive gestures, was atrophic. The researchers speculated that because they varied so little, the cognitive scores failed to correlate with regional volume loss: Out of a maximum of 36 points on the nontransitive gesture score, noncarriers scored an average of 35.7 points, while carriers managed 34.9.

“This is an important study in a large cohort of presymptomatic C9 mutation carriers to further define the preclinical status of C9 mutation carriers,” wrote Manuela Neumann of the German Center for Neurodegenerative Diseases in Tübingen. She noted the obvious limitation of the study was its cross-sectional design. “It remains to be seen which, if any, of the observed changes will progress until disease onset and if some changes might reflect developmental alterations. It will be also particularly interesting to learn about potential differences between patients presenting with ALS versus FTLD,” she wrote. The researchers await longitudinal data on this cohort.—Jessica Shugart


  1. This large cohort of presymptomatic C9ORF72 expansion carriers shows a surprising and interesting new finding of lower praxis scores. Future longitudinal studies will be needed to determine whether the early gray-matter and white-matter deficits also seen in presymptomatic C9ORF72 expansion carriers reflect developmental differences or early neurodegenerative changes.

Make a Comment

To make a comment you must login or register.


News Citations

  1. First Data from GENFI1: Brain’s Insula Region Shrinks A Decade Before FTD

Paper Citations

  1. . Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis. Lancet Neurol. 2015 Mar;14(3):253-62. Epub 2015 Feb 4 PubMed.
  2. . Brain morphologic changes in asymptomatic C9orf72 repeat expansion carriers. Neurology. 2015 Nov 17;85(20):1780-8. Epub 2015 Oct 23 PubMed.
  3. . Network degeneration and dysfunction in presymptomatic C9ORF72 expansion carriers. Neuroimage Clin. 2017;14:286-297. Epub 2016 Dec 10 PubMed.
  4. . Cognition and gray and white matter characteristics of presymptomatic C9orf72 repeat expansion. Neurology. 2017 Sep 19;89(12):1256-1264. Epub 2017 Aug 30 PubMed.
  5. . Patterns of gray matter atrophy in genetic frontotemporal dementia: results from the GENFI study. Neurobiol Aging. 2018 Feb;62:191-196. Epub 2017 Oct 19 PubMed.
  6. . Structural and functional brain signatures of C9orf72 in motor neuron disease. Neurobiol Aging. 2017 Sep;57:206-219. Epub 2017 Jun 6 PubMed.

Further Reading

Primary Papers

  1. . Early Cognitive, Structural, and Microstructural Changes in Presymptomatic C9orf72 Carriers Younger Than 40 Years. JAMA Neurol. 2018 Feb 1;75(2):236-245. PubMed.