Characterizing circulating biomarkers for childhood dementia disorders: A scoping review of clinical trials

Affiliations

¹ Department of Neurology, The Sydney Children's Hospitals Network, Sydney, Australia; Discipline of Paediatrics and Child Health, School of Clinical Medicine, UNSW Medicine and Health, The University of New South Wales, Sydney, Australia; UNSW RNA Institute, The University of New South Wales, Sydney, Australia. Electronic address: a.dsilva@unsw.edu.au.
² Department of Neurology, The Sydney Children's Hospitals Network, Sydney, Australia; Discipline of Paediatrics and Child Health, School of Clinical Medicine, UNSW Medicine and Health, The University of New South Wales, Sydney, Australia.
³ Sydney Children's Hospitals' Network, Westmead, NSW 2145, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
⁴ Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Clinical School, NSW, Australia.
⁵ Department of Genetic Medicine, Westmead Hospital, Westmead, NSW 2145, Australia; Faculty of Medicine and Health, University of Sydney, NSW, Australia.
⁶ Children, Young People and Families Directorate of Hunter New England Local Health District and John Hunter Children's Hospital, New Lambton Heights, NSW 2305, Australia.
⁷ Childhood Dementia Initiative, Brookvale, NSW, 2100, Australia.
⁸ Department of Neurology, The Sydney Children's Hospitals Network, Sydney, Australia; Discipline of Paediatrics and Child Health, School of Clinical Medicine, UNSW Medicine and Health, The University of New South Wales, Sydney, Australia; UNSW RNA Institute, The University of New South Wales, Sydney, Australia.

PMID: 39948021
PMCID: PMC12014410
DOI: 10.1016/j.neurot.2025.e00546

Characterizing circulating biomarkers for childhood dementia disorders: A scoping review of clinical trials

Arlene D'Silva et al. Neurotherapeutics. 2025 Mar.

. 2025 Mar;22(2):e00546.

doi: 10.1016/j.neurot.2025.e00546. Epub 2025 Feb 12.

Authors

Affiliations

¹ Department of Neurology, The Sydney Children's Hospitals Network, Sydney, Australia; Discipline of Paediatrics and Child Health, School of Clinical Medicine, UNSW Medicine and Health, The University of New South Wales, Sydney, Australia; UNSW RNA Institute, The University of New South Wales, Sydney, Australia. Electronic address: a.dsilva@unsw.edu.au.
² Department of Neurology, The Sydney Children's Hospitals Network, Sydney, Australia; Discipline of Paediatrics and Child Health, School of Clinical Medicine, UNSW Medicine and Health, The University of New South Wales, Sydney, Australia.
³ Sydney Children's Hospitals' Network, Westmead, NSW 2145, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
⁴ Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Clinical School, NSW, Australia.
⁵ Department of Genetic Medicine, Westmead Hospital, Westmead, NSW 2145, Australia; Faculty of Medicine and Health, University of Sydney, NSW, Australia.
⁶ Children, Young People and Families Directorate of Hunter New England Local Health District and John Hunter Children's Hospital, New Lambton Heights, NSW 2305, Australia.
⁷ Childhood Dementia Initiative, Brookvale, NSW, 2100, Australia.
⁸ Department of Neurology, The Sydney Children's Hospitals Network, Sydney, Australia; Discipline of Paediatrics and Child Health, School of Clinical Medicine, UNSW Medicine and Health, The University of New South Wales, Sydney, Australia; UNSW RNA Institute, The University of New South Wales, Sydney, Australia.

PMID: 39948021
PMCID: PMC12014410
DOI: 10.1016/j.neurot.2025.e00546

Abstract

Childhood dementias, a group of neurological disorders are characterised by neurocognitive decline, with physical and psychosocial impacts for individuals. With therapy available for <5 % of childhood dementias, there is a high level of unmet need. Integration of biomarkers in clinical trials are important to characterize distinctive biological activities and interrogate targets for therapeutic development. This study reviewed four clinical trial registries to examine circulating biomarkers in childhood dementias. Findings from 262 studies were synthesized across 49/72 (68 %) childhood dementia disorders. Disease-related biomarkers were associated with 1) the primary pathophysiology 2) downstream pathogenic events 3) drug-related pharmacokinetics, safety and/or tolerability. The predominant biological measures were metabolites linked to the primary pathophysiological pathway (102 measures, 185 studies), while use of cytoskeletal proteins (3 measures, 15 studies), inflammatory mediators (19 measures, 24 studies), oxidative stress-related analytes (15 measures, 8 studies), neurotransmitters or related neuro-metabolites (3 measures, 5 studies) were limited. A range of potential biomarkers are used in clinical trials; however, their use is inconsistent and under utilised among conditions. Development of a panel of biomarkers has potential to interrogate and link shared biological pathways across the heterogeneity of childhood dementias to exert a significant impact for the development of disease-modifying therapies.

Keywords: Biomarkers; Childhood dementia; Clinical trials; Endpoints; Metabolomics; Proteomics.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest Kristina Elvidge is the Head of Research at the Childhood Dementia Initiative. All other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

**Fig. 1**
PRISMA flow diagram - exclusion and inclusion criteria for studies reviewed.

**Fig. 2**
**The number of clinical trials incorporating circulating biomarkers in childhood dementia disorders.** The individual conditions are listed, according to their disease categories (**Inborn Errors of Metabolism**, their subset **Lysosomal Storage Disorders**, and those **Otherwise Classified**), as follows: **Glycoproteinosis (18):** Alpha-Mannosidosis (16): Aspartylglucosaminuria (AGU) (4), Fucosidosis (Type I and II) (3), Galactosialidosis (Cathepsin A Mutation) (1), Mucolipidosis Type I (Sialidosis) (1), Mucolipidosis Type II (i-Cell Disease) (2), Mucolipidosis Type IV (2)., α-N-acetylgalactosaminidase Deficiency (Schindler Disease Type I) (1). **Lysosomal storage disorders of lipid metabolism and transport (76):** Acid sphingomyelinase deficiency (Niemann Pick A) (3), Gaucher Type 2 (2), Gaucher Type 3 (12), Globoid Cell Leukodystrophy (Krabbe Disease) (9), GM1 gangliosidosis (7), GM2 gangliosidosis – non-specified (10), GM2 gangliosidosis (Tay-Sachs disease) (1), Metachromatic leukodystrophy (27), Niemann-Pick C (19), Saposin C Deficiency (1). **Mucopolysaccharidoses (79):** MPS I Hurler Syndrome (25). MPS II Hunter Syndrome (23), MPS III Sanfilippo Syndrome (33), MPS VII Sly Syndrome (6). **Other lysosomal diseases (10):** Neuronal Ceroid Lipofuscinoses (Batten Disease) (10). **Other disorders of lipid metabolism and transport (5):** Abetalipoproteinaemia (1), Cerebrotendinous Xanthomatosis (4). **Disorders of amino acid and other organic acid metabolism (6):** Canavan Disease (5), Sulfite/Sulphite Oxidase Deficiency (1). **Vitamin-responsive inherited metabolic disorders (6):** Cobalamin C Disease/Deficiency (1), Molybdenum Cofactor Deficiency (5). **Disorders of mineral absorption and transport (12):** Wilson disease (12). **Peroxisomal disease (16):** X-linked adrenoleukodystrophy (13), Zellweger Spectrum Disorder (4). **Mitochondrial disorders (12):** Kearns-Sayre syndrome (3), Leigh disease (5), MELAS (8), POLG-related disease (1). **Other inherited metabolic disorders (11):** Congenital disorders of glycosylation (8), Pyruvate dehydrogenase deficiency (3). **Leukodystrophies not otherwise categorized (4):** Alexander Disease (Type I) (1), Pelizaeus Merzbacher Disease (2), Vanishing White Matter Disease (1). **Neurodegeneration with brain iron accumulation (5):** Beta propeller protein associated neurodegeneration (BPAN) (1), Coenzyme A synthase protein-associated neurodegeneration (COASY) (1), Pantothenate kinase-associated neurodegeneration (PKAN) (5). **Neurodegenerative diseases not otherwise categorized (22):** Cockayne Syndrome (1), Giant axonal neuropathy (1), Huntington's Disease (Juvenile Form) (1), Infantile Neuroaxonal Dystrophy (1), Rett Syndrome (18).

**Fig. 3**
**Summation of disease-related biomarker use across childhood dementia condition categories.** The ‘Total Studies’ refers to the number of studies which examined conditions in that category. Some studies examined multiple categories. The percentage is calculated as the number of times that biomarker theme was used in a study of that condition category, given in parentheses, divided by ‘Total Studies’ for that condition category.

See this image and copyright information in PMC

References

1. Nevin S.M., McGill B.C., Kelada L., Hilton G., Maack M., Elvidge K.L., et al. The psychosocial impact of childhood dementia on children and their parents: a systematic review. Orphanet J Rare Dis. 2023;18(1) - PMC - PubMed
1. Elvidge K.L., Christodoulou J., Farrar M.A., Tilden D., Maack M., Valeri M., et al. The collective burden of childhood dementia: a scoping review. Brain. 2023;146(11):4446–4455. - PMC - PubMed
1. Nunn K., Williams K., Ouvrier R. The australian childhood dementia study. Eur Child Adolesc Psychiatr. 2002;11(2):63–70. - PubMed
1. Djafar J.V., Johnson A.M., Elvidge K.L., Farrar M.A. Childhood dementia: a collective clinical approach to advance therapeutic development and care. Pediatr Neurol. 2023;139:76–85. - PubMed
1. Fermaglich L.J., Miller K.L. A comprehensive study of the rare diseases and conditions targeted by orphan drug designations and approvals over the forty years of the orphan drug act. Orphanet J Rare Dis. 2023;18(1):163. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Characterizing circulating biomarkers for childhood dementia disorders: A scoping review of clinical trials

Affiliations

Characterizing circulating biomarkers for childhood dementia disorders: A scoping review of clinical trials

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical