Risk Genes Influence Brain Connectivity in Preclinical FTD

Previous studies indicated that polymorphisms in the TMEM106B gene exacerbate frontotemporal dementia caused by progranulin mutations, advancing disease onset by more than a decade. Now, new research strengthens the case for that synergy, and provides clues to how it works. In the December 16 JAMA Neurology, researchers led by Barbara Borroni at the University of Brescia, Italy, report that brain connections weakened by progranulin mutations are further compromised in patients who also carry the TMEM106B risk allele. By contrast, this allele did not affect connectivity in healthy controls. If the results need to be replicated in a larger group, they bolster the hypothesis that TMEM106B modulates disease severity and onset in people with progranulin mutations, Borroni told Alzforum.

Commentators agreed that these data complement genetic and molecular studies that showed a relationship between the genes. “This extends efforts to define the biology of the TMEM106B polymorphism. I think this paper will fuel interest in doing additional studies,” said John Trojanowski at the University of Pennsylvania, Philadelphia. Rosa Rademakers at the Mayo Clinic in Jacksonville, Florida, called the data exciting. “After the initial discovery of TMEM106B there had been some conflicting replication studies, but this new data, combined with recent functional data, further confirm the importance of this protein in FTD,” she wrote to Alzforum.

Progranulin mutations that disrupt protein function account for about 20 percent of familial and up to 10 percent of sporadic FTD (see Apr 2007 conference story; Rademakers et al., 2007). Scientists are still trying to find out exactly how a lack of progranulin leads to disease, although some researchers have pointed to the protein’s neurotrophic properties and role in curbing inflammation (see Mar 2011 news story; Oct 2012 news story). The story got more interesting when researchers identified polymorphisms that pump up expression of TMEM106B, a transmembrane protein found in lysosomes, more than doubling the risk for FTD (see Feb 2010 news story). Intriguingly, these polymorphisms associated with low levels of plasma progranulin (see Cruchaga et al., 2011; Finch et al., 2011). Recent work suggests that TMEM106B regulates trafficking of progranulin, with too much TMEM106B keeping progranulin levels high in the cell (see Aug 2012 news story). It is unclear how this relates to plasma progranulin.

Borroni and colleagues wanted to find out if TMEM106B also interacted with progranulin to modulate brain systems. In previous studies, the authors found that, in cognitively healthy adults who carry a progranulin mutation, brain connectivity was changed up to two decades before they would be expected to develop symptoms (see Borroni et al., 2012). In the current study, first author Enrico Premi performed resting-state functional magnetic resonance imaging (fMRI) on 17 progranulin carriers and 14 healthy controls. All participants were cognitively healthy, with an average age of 40. Consistent with the earlier work, in mutation carriers connectivity was weaker in the left frontoparietal network and stronger in the executive network compared with controls. Four people who also carried the TMEM106B risk polymorphism showed additional weakening in frontoparietal connections, as well as in the ventral salience network. These networks control the type of judgment and reasoning abilities that are most affected by FTD.

While the number of patients with TMEM106B risk alleles was small, the cross-sectional data hints that TMEM106B genotyping could help refine the prognosis for people with progranulin mutations, Borroni said. She will follow this cohort to investigate their trajectory of brain changes as symptoms appear, and also wants to replicate the findings in a larger group.

Exactly how these gene variants might change the brain’s connective pathways remains a mystery. Because progranulin promotes growth, its lack might lead to cellular damage and atrophy, Borroni speculated. Progranulin mutation carriers accumulate aggregates of the RNA-binding protein TDP-43 in the brain. These foci are pathological features of FTD and motor neuron disease. Trojanowski noted that a recent collaborative study with Heiko Braak's lab at the University of Ulm, Germany, hints that TDP-43 may spread across the brain (see Nov 2013 conference story; Brettschneider et al., 2013), similar to the way other pathogenic proteins are believed to propagate from cell to cell along neuronal pathways (see Aug 2013 conference story). If so, the transmission of TDP-43 might be disrupting connections downstream from TMEM106B and progranulin mutations, he suggested.

Erosion of brain connections may be a general feature of neurodegenerative disease. In Alzheimer’s as well, connectivity weakens in brain networks years before symptoms, and correlates with other early biomarkers (see Jul 2012 news story; Jul 2013 news story; Aug 2013 news story). Functional MRI is far from being ready to be used broadly as a validated biomarker, but because of its sensitivity to early changes, it is increasingly being explored in longitudinal studies and some clinical trials.—Madolyn Bowman Rogers

Comments

  1. In this paper, Premi et al. describe the effect of the TMEM106B risk variant on functional connectivity in progranulin gene (GRN) mutation carriers, more specifically among asymptomatic carriers. This study provides very valuable information about the early disease processes in frontotemporal dementia. However, such studies are difficult to perform because the frequency of these pathogenic mutations in the general population is very low and the identification of asymptomatic carriers very challenging. In any case, Premi et al. identified 17 asymptomatic individuals with the GRN Thr272fs mutation, and compared them to 14 noncarriers. Although these numbers would in most cases be too small to perform any kind of statistical comparison, the authors used a very clever design to increase the power of the analysis: They used genetic data to confirm that all the individuals come from a common genetic ancestor. This decreased the general heterogeneity of the subjects, and therefore increased the power. The authors found significantly reduced brain connectivity in the frontoparietal network in the GRN carriers versus the noncarriers. They also found that among the asymptomatic GRN carriers, those with the TMEM106 risk variant had even further losses of brain connectivity in specific brain areas. I think these findings clearly support the notion that the brain changes and pathology occur much earlier than the clinical symptoms. However, we would all like to know what the expected/estimated age at onset of the GRN carriers is, and that is something this study could not provide. Finally, this study also confirms that the TMEM106B is an important gene in modulating the risk of FTLD.

    View all comments by Carlos Cruchaga

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References

News Citations

  1. Salzburg: Getting to Know Progranulin, the New Heavy
  2. Progranulin—Curbs Phagocyte Appetites, Protects Neurons?
  3. Microglial Progranulin Douses Neural Inflammation
  4. Genetics of FTD: New Gene, PGRN Variety, and a Bit of FUS
  5. The Four Stages of TDP-43 Proteinopathy
  6. Communication Breakdown: Multiple Networks Decline in AD Brains
  7. Atrophy of Distinct Brain Networks May Explain Alzheimer’s Variants
  8. Brain Connectivity Reveals Preclinical Alzheimer’s Disease

Alzpedia Citations

  1. Progranulin

Paper Citations

  1. Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, Spina S, Coppola G, Karydas AM, Stewart H, Johnson N, Hsiung GY, Kelley B, Kuntz K, Steinbart E, Wood EM, Yu CE, Josephs K, Sorenson E, Womack KB, Weintraub S, Pickering-Brown SM, Schofield PR, Brooks WS, Van Deerlin VM, Snowden J, Clark CM, Kertesz A, Boylan K, Ghetti B, Neary D, Schellenberg GD, Beach TG, Mesulam M, Mann D, Grafman J, Mackenzie IR, Feldman H, Bird T, Petersen R, Knopman D, Boeve B, Geschwind DH, Miller B, Wszolek Z, Lippa C, Bigio EH, Dickson D, Graff-Radford N, Hutton M. Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-->T (Arg493X) mutation: an international initiative. Lancet Neurol. 2007 Oct;6(10):857-68. PubMed.
  2. Cruchaga C, Graff C, Chiang HH, Wang J, Hinrichs AL, Spiegel N, Bertelsen S, Mayo K, Norton JB, Morris JC, Goate A. Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels. Arch Neurol. 2011 May;68(5):581-6. PubMed.
  3. Finch N, Carrasquillo MM, Baker M, Rutherford NJ, Coppola G, Dejesus-Hernandez M, Crook R, Hunter T, Ghidoni R, Benussi L, Crook J, Finger E, Hantanpaa KJ, Karydas AM, Sengdy P, Gonzalez J, Seeley WW, Johnson N, Beach TG, Mesulam M, Forloni G, Kertesz A, Knopman DS, Uitti R, White CL, Caselli R, Lippa C, Bigio EH, Wszolek ZK, Binetti G, Mackenzie IR, Miller BL, Boeve BF, Younkin SG, Dickson DW, Petersen RC, Graff-Radford NR, Geschwind DH, Rademakers R. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology. 2011 Feb 1;76(5):467-74. PubMed.
  4. Borroni B, Alberici A, Cercignani M, Premi E, Serra L, Cerini C, Cosseddu M, Pettenati C, Turla M, Archetti S, Gasparotti R, Caltagirone C, Padovani A, Bozzali M. Granulin mutation drives brain damage and reorganization from preclinical to symptomatic FTLD. Neurobiol Aging. 2012 Oct;33(10):2506-20. Epub 2011 Nov 29 PubMed.
  5. Brettschneider J, Del Tredici K, Toledo JB, Robinson JL, Irwin DJ, Grossman M, Suh E, Van Deerlin VM, Wood EM, Baek Y, Kwong L, Lee EB, Elman L, McCluskey L, Fang L, Feldengut S, Ludolph AC, Lee VM, Braak H, Trojanowski JQ. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol. 2013 Jul;74(1):20-38. PubMed.

Other Citations

  1. Aug 2013 conference story

External Citations

  1. Aug 2012 news story

Further Reading

Primary Papers

  1. Premi E, Formenti A, Gazzina S, Archetti S, Gasparotti R, Padovani A, Borroni B. Effect of TMEM106B Polymorphism on Functional Network Connectivity in Asymptomatic GRN Mutation Carriers. JAMA Neurol. 2013 Dec 16; PubMed.

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