Cooper-Knock J, Green C, Altschuler G, Wei W, Bury JJ, Heath PR, Wyles M, Gelsthorpe C, Highley JR, Lorente-Pons A, Beck T, Doyle K, Otero K, Traynor B, Kirby J, Shaw PJ, Hide W. A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2017 Mar 16;5(1):23. PubMed.
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Weizmann Institute of Science
This paper by Cooper-Knock and colleagues describes an extremely important study in understanding ALS, and in searching for prognostic biomarkers of ALS progression. Overall, the work emphasizes that ALS, not only in animal models but also in patients, is not a cell (motor neuron) or tissue (CNS) autonomous disease, and involves the local microglia, and the systemic immune system. In addition, this is the first study to use a robust and non-biased genomic approach to search for biomarkers that correlate with disease severity/progression, despite the heterogeneity of the disease.
The authors, by using a systematic and non-biased approach, identified gene clusters, modules which change in the diseased motor neurons during disease progression and that correlated with a separate module that characterizes the immune response in ALS patients. Subsequently, they found that the immunological module was specifically associated with changes in microglia. Among the most robust changes in microglia that were found to correlate with disease severity were expression of Trem2, LILRA2, ITGB2, and CEBPD. Finally, they found that TREM2 expression is reflected in the CSF, and the other three markers, in the circulating immune cells.
Overall, this study represents a first and important non-biased step in searching for disease markers in ALS that can be measured in accessible tissues, and thus can be used to predict disease progression, and eventually enable personalized medicine. The finding that sTREM2 increased in the CSF at early disease stages is a sign of disease onset, and its rapid elevation thereafter is a prognostic sign of slow disease progression, which suggests its potential beneficial effect in coping with the disease. This is consistent with the reported positive role of TREM2 in Alzheimer’s disease. These results encourage the use of Cooper-Knock's approach to search for similar biomarkers in other neurodegenerative diseases whose etiology and course are still poorly understood, as it may lead not only to identification of additional biomarkers, but also provide therapeutic targets.
View all comments by Michal SchwartzWashington University in St. Louis
Overall this is an interesting article, and Cooper-Knock and colleagues use a powerful system biology approach to identify potential molecules that could serve as biomarkers for disease progression in ALS. However, I would be very cautious in the interpretation of some of the results.
In the first part of the study, it is surprising that from transcriptome analysis of spinal cord motor neurons and of lymphoblastoid cell lines (immortalized B cells) from ALS patients they find a set of genes that are related to microglia and macrophages. This is a little bit puzzling to me. They explain this by saying that in the laser capture procedure they may have taken some microglial cells along with the motor neurons. I am not sure this is a really good explanation. In addition, they also used transcriptome data from lymphoblastoid cell lines, which are not completely comparable to microglia/macrophages and they do not express TREM2.
The researchers go on to measure levels of soluble TREM2 (sTREM2) in the cerebrospinal fluid (CSF) of a cohort of ALS patients and control individuals with non-inflammatory neurological disease. Interestingly, levels of sTREM2 are elevated in the CSF of patients with ALS compared to controls. This is very likely reflecting microglia activation in ALS patients as a response to the ongoing neurodegenerative process. This also recapitulates what was observed in patients with Alzheimer’s disease (AD) by our and other groups. Next, the authors show that CSF sTREM2 levels are higher in early versus late stages in ALS (Figure 4b in the paper). I would interpret these results with caution because the difference between early versus late ALS seems to be driven by the presence of an outlier in the group of early ALS. These results would need to be confirmed in a larger group of patients. It is interesting that these data are paralleling a model proposed in AD by other groups with higher levels of CSF sTREM2 in early AD cases and a decline at later stages of the disease (Suarez-Calvet 2016 and 2016). In my opinion, these data also require further confirmation in larger and possibly longitudinal data sets from AD patients.
Finally, Cooper-Knock and colleagues found that levels of sTREM2 are positively correlated with disease duration in a subset of patients with late ALS, as if microglia activation could have a neuroprotective effect and slow down disease progression. The proposed model of a “U-shaped curve” for sTREM2 CSF levels (high in early stages and then levels that gradually decline at later stages at a possible different pace) would need to be confirmed in additional studies with increased number of subjects.
References:
Suárez-Calvet M, Araque Caballero MÁ, Kleinberger G, Bateman RJ, Fagan AM, Morris JC, Levin J, Danek A, Ewers M, Haass C, Dominantly Inherited Alzheimer Network. Early changes in CSF sTREM2 in dominantly inherited Alzheimer's disease occur after amyloid deposition and neuronal injury. Sci Transl Med. 2016 Dec 14;8(369):369ra178. PubMed.
Suárez-Calvet M, Kleinberger G, Araque Caballero MÁ, Brendel M, Rominger A, Alcolea D, Fortea J, Lleó A, Blesa R, Gispert JD, Sánchez-Valle R, Antonell A, Rami L, Molinuevo JL, Brosseron F, Traschütz A, Heneka MT, Struyfs H, Engelborghs S, Sleegers K, Van Broeckhoven C, Zetterberg H, Nellgård B, Blennow K, Crispin A, Ewers M, Haass C. sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer's disease and associate with neuronal injury markers. EMBO Mol Med. 2016 May 2;8(5):466-76. PubMed.
View all comments by Laura PiccioUniversity of Sheffield
Laura Piccio makes some good points regarding our work and we thank her for her comments. However, I would like to clarify a point regarding an outlier in our CSF study. Dr. Piccio draws attention to the outlier in the measurement of CSF soluble TREM2 in early ALS; this was noted at the time of analysis and its effect was removed by using a rank-based analysis rather than absolute values of measured soluble TREM2. The statistically significant difference quoted in the manuscript was derived in this way without a significant effect from the outlier sample.
It is agreed that our proposed biomarkers require confirmation in larger sample groups, however, we believe the central tenant of our paper is robust—genes expressed in proportion to motor neuron pathology identify a gene set that is associated with microglial function, and has prognostic potential.
View all comments by Johnathan Cooper-KnockUniversity of Ulm
The methods and models used in this paper are very impressive. However, at the moment a clear-cut diagnostic use of these biomarker candidates is difficult to see. Possibly follow-up investigations of these candidates will prove a clinical application.
View all comments by Markus OttoBarcelonaBeta Brain Research Center; Hospital del Mar - Barcelona
Biomedizinisches Centrum (BMC), Biochemie & Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
The interesting study of Cooper-Knock et al. highlights the importance of a TREM2-dependent, potentially protective, microglia function in the pathogenesis of ALS. This also supports a general function of TREM2 and microglia as modifiers for several distinct neurodegenerative diseases.
Strikingly, changes in the levels of CSF sTREM2 follow a similar pattern to that we had observed in sporadic Alzheimer's disease and within the DIAN cohort, that is, a slight, but significant, increase in early stages of the disease.
Moreover, this paper also shows that in later stages of ALS, higher levels of CSF sTREM2 positively correlate with longer disease duration. Thus, TREM2 may indeed have a protective function as suggested by the loss-of-function character of its disease-associated mutations. Nevertheless, further work in larger and specifically in longitudinal cohorts will be required to finally prove the hypothesis that levels of CSF sTREM2 predict a better or worse outcome not only in ALS but also in AD and other neurodegenerative diseases.
View all comments by Christian HaassMake a Comment
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