Saloner R, Staffaroni A, Dammer E, Johnson EC, Paolillo E, Wise A, Heuer H, Forsberg L, Lago AL, Webb J, Vogel J, Santillo A, Hansson O, Kramer J, Miller B, Li J, Loureiro J, Sivasankaran R, Worringer K, Seyfried N, Yokoyama J, Seeley W, Spina S, Grinberg L, VandeVrede L, Ljubenkov P, Bayram E, Bozoki A, Brushaber D, Considine C, Day G, Dickerson B, Domoto-Reilly K, Faber K, Galasko D, Geschwind D, Ghoshal N, Graff-Radford N, Hales C, Honig L, Hsiung GY, Huey E, Kornak J, Kremers W, Lapid M, Lee S, Litvan I, McMillan C, Mendez M, Miyagawa T, Pantelyat A, Pascual B, Paulson H, Petrucelli L, Pressman P, Ramos E, Rascovsky K, Roberson E, Savica R, Snyder A, Sullivan AC, Tartaglia C, Vandebergh M, Boeve B, Rosen H, Rojas J, Boxer A, Casaletto K. Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration. Res Sq. 2024 Mar 28; PubMed.
Recommends
Please login to recommend the paper.
Comments
VU University Medical Center
This is impressive work. The relatively large number of individuals per genetic subtype included explains the large number of proteins identified. The paper is a very valuable source for other proteomics studies. There are not so many proteomics studies published yet for FTD, and having a benchmark such as this study is therefore very valuable.
The within-genetic subtype analyses compared presymptomatic changes with those of symptomatic changes. The proteins observed for the presymptomatic phase are interesting as they reveal “cleaner’’ biology, i.e., before the genetic subtype-specific biology is masked by overt neurodegenerative pathology occurring in the symptomatic stage. The protein changes, and the modules identified in these presymptomatic changes, are to me the most germane findings of the study for understanding the biology of each subtype.
It is remarkable that the neurodegeneration markers that are increased across all stages highly overlap with those observed in AD, although there are clearly different symptoms between these diseases. This says to me that even with the very good coverage of proteins in the paper, there are likely still a lot of proteins to be identified. Perhaps affinity based -omics arrays such as PEA and Somascan can add to the full biological picture.
View all comments by Charlotte TeunissenGlobal Brain Health Institute
This is a very impactful paper.
The authors found distinct and shared proteomic alterations across genetic FTD subtypes. Each genetic FTD mutation (C9ORF72, GRN, MAPT) displayed unique CSF proteomic changes. Some proteins were altered across all three subtypes and in Alzheimer’s Disease, suggesting common neurodegeneration mechanisms. Lysosomal protein levels were markedly reduced in MAPT carriers but not in the other groups. Several biomarkers were common to all FTD subtypes and AD, including Neuronal Pentraxin 2, Fatty Acid Binding Protein 3, UCHL1, and 14-3-3 proteins (YWHAZ, YWHAG, YWHAE).
Some biomarkers were unique to specific FTD subtypes. Some of these displayed early proteomic changes in presymptomatic FTD mutation carriers. Moreover, they found strong correlations between disease severity and cognitive decline, with NfL showing strong associations with disease severity and brain atrophy. WGCNA revealed protein clusters linked to synaptic dysfunction, glial responses, and lysosomal impairment.
These clusters were strongly correlated with Mini-Mental State Examination (MMSE) scores, disease progression, and brain volume loss. The identified proteomic signatures in presymptomatic carriers that could be early biomarkers for tracking disease onset, with candidates for monitoring disease progression. The authors also found distinctive protein changes that differentiate FTD subtypes from AD.
Proteomic comparisons with AD may refine differential diagnoses in ambiguous cases. Their findings highlight lysosomal dysfunction as a potential therapeutic target. Additionally, integrating proteomic data with imaging and genetic datasets could enhance biomarker discovery.
One of the most notable and (a bit unexpected) findings was the proteomic similarities between FTD and AD.
This study provides the largest and most comprehensive proteomic analysis of genetic FTD, identifying shared and unique markers across genetic subtypes, advancing the field toward precision biomarkers.
View all comments by Agustin IbanezMemory and Aging Center, Weill Insititute for Neurosciences, University of California, San Francisco
This is an important study for fluid biomarker development in FTD. The results could support further diagnostic and therapeutic development in FTD, a condition with no cure and for which no specific diagnostic test exist.
The study in this European cohort replicates the findings of its North American counterpart ALLFTD, which also identified similar mutation-specific CSF proteomic signatures in familial and pathology-confirmed sporadic cases (e.g., extracellular matrix, synaptic function, and autophagy), as presented in the last International Society for Frontotemporal Dementia scientific meeting in September 2024 (Saloner et al., 2024). The ALLFTD study interrogated the levels of twice as many CSF targets and identified an additional strong signal from RNA splicing proteins. The changes in MAPT mutation carriers involving synapse formation and axonal guidance suggest a major role of these neuronal pathways in tauopathies, which has been previously seen in progressive supranuclear palsy, a sporadic and relatively more common FTD tauopathy (Wise et al., 2024). Similar to the previous CSF proteomics studies in FTD, the study by Sogorb-Esteve and colleagues showcases the power of WGCNA and other novel data analysis techniques, that are becoming the standard for the analysis of proteomics signatures in FTD.
A limitation of this and the previous proteomics studies in FTD mentioned above are that the quantitative platforms only capture a fraction of the CSF proteome (about 10 percent in Sogorb-Esteve et al.’s study). There may be biases imposed by what analytes are measured. For example, many nuclear or mitochondrial pathways and proteins were not represented in this mass-spectrometry study. Also, these proteomic platforms quantify native proteins, but it is possible that a stronger signal would be obtained when measuring proteins with post-translational modifications, like Aβ and phosphorylated tau, which are useful in Alzheimer’s disease as opposed to the native proteins.
Future proteomics studies should also tackle products of cryptic splicing, a fundamental pathobiological process, especially in forms of FTD with FTD-43 pathology. Also, although findings in CSF are great progress, the field needs blood-based biomarkers, which are more easily implemented on clinical grounds, especially in clinical trials. There is also a need to run proteomics studies in diverse populations of non-European descent.
The field of clinical FTD research is living a golden era and more progress on biomarkers and therapeutics will likely be seen in the upcoming years for this devastating group of diseases.
References:
Saloner R, Staffaroni A, Dammer E, Johnson EC, Paolillo E, Wise A, Heuer H, Forsberg L, Lago AL, Webb J, Vogel J, Santillo A, Hansson O, Kramer J, Miller B, Li J, Loureiro J, Sivasankaran R, Worringer K, Seyfried N, Yokoyama J, Seeley W, Spina S, Grinberg L, VandeVrede L, Ljubenkov P, Bayram E, Bozoki A, Brushaber D, Considine C, Day G, Dickerson B, Domoto-Reilly K, Faber K, Galasko D, Geschwind D, Ghoshal N, Graff-Radford N, Hales C, Honig L, Hsiung GY, Huey E, Kornak J, Kremers W, Lapid M, Lee S, Litvan I, McMillan C, Mendez M, Miyagawa T, Pantelyat A, Pascual B, Paulson H, Petrucelli L, Pressman P, Ramos E, Rascovsky K, Roberson E, Savica R, Snyder A, Sullivan AC, Tartaglia C, Vandebergh M, Boeve B, Rosen H, Rojas J, Boxer A, Casaletto K. Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration. Res Sq. 2024 Mar 28; PubMed.
Wise A, Li J, Yamakawa M, Loureiro J, Peterson B, Worringer K, Sivasankaran R, Palma JA, Mitic L, Heuer HW, Lario-Lago A, Staffaroni AM, Clark A, Taylor J, Ljubenkov PA, Vandevrede L, Grinberg LT, Spina S, Seeley WW, Miller BL, Boeve BF, Dickerson BC, Grossman M, Litvan I, Pantelyat A, Tartaglia MC, Zhang Z, Wills AA, Rexach J, Rojas JC, Boxer AL, as the 4-Repeat Tauopathy Neuroimaging Initiative. CSF Proteomics in Patients With Progressive Supranuclear Palsy. Neurology. 2024 Aug 13;103(3):e209585. Epub 2024 Jul 3 PubMed.
View all comments by Julio RojasMake a Comment
To make a comment you must login or register.