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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT06321588
Other study ID # GR-2021-12373134
Secondary ID
Status Recruiting
Phase
First received
Last updated
Start date May 10, 2023
Est. completion date June 30, 2026

Study information

Verified date March 2024
Source Azienda Usl di Bologna
Contact Maria Pia Giannoccaro, Dr.
Phone +390514966112
Email mariapia.giannoccaro@ausl.bologna.it
Is FDA regulated No
Health authority
Study type Observational

Clinical Trial Summary

The goal of this observational study is to investigate the frequency and the possible pathogenic role of neuronal synaptic antibodies (NSAb) in patients with cognitive impairment (CI). The main questions it aims to answer are: 1. the frequency and associated features of NSAb in patients with CI and the usefulness of a clinical score in improving autoimmune dementia (AID) diagnosis; 2. the clinical significance of NSAb in patients with CI not fulfilling the autoimmune encephalitis (AE) criteria and serum NSAb (NSAb-pos-CI); 3. the impact of blood-brain-barrier (BBB) dysfunction on their pathogenicity.


Description:

AE can mimic dementia and, contrarily to neurodegenerative dementia syndromes, affected patients can improve with timely immunotherapies. Consensus-based diagnostic criteria for AE help to select patients for antibody testing. However, encephalitis signs can be absent, particularly in the elderly, and AE can present with slowly progressing CI mimicking classical neurodegenerative diseases, misleading the diagnostic process. Data on the prevalence of NSAb and AE in unselected patients with CI are sparse and mostly affected by retrospective design, small cohorts, and antibody assay shortcomings. There is an urgent need to define the frequency of NSAb and AE in CI patients and elucidate the associated clinical, laboratory and imaging features. Filling these gaps is the first aim of this project. This will allow the early identification and the best management of patients with AID. On the other hand, a proportion of CI patients have NSAb and do not fit the AE criteria (NSAb-pos-CI). These NSAb are often in the serum, and not in the Cerebrospinal Fluid (CSF), or belong to the Immunoglobulin A/M (Ig A/M) subclasses, as opposite to the AE-associated Immunoglobulin G (IgG) subclass, thus triggering questions about their clinical and therapeutic implications. As NSAb can be found at low titers in the serum of healthy controls, a hypothesis explaining their pathogenicity relies on dysfunctions of the BBB, in a context of indolent inflammation, that might allow the antibodies to reach the Central Nervous System (CNS). Alternatively, NSAb may not be directly pathogenic and could even be secondary to an ongoing neurodegenerative process. However, even in this context, known and unknown NSAb, could still contribute to the clinical phenotype, modulating the disease progression or the presence of additional clinical features (i.e. psychiatric symptoms). Understanding if these serum NSAb, along with other factors such as inflammation and BBB alterations, have a role in modifying the disease trajectory, i.e. accelerating the neurodegeneration and CI progression, is the other main goal. This project will represent a chance to clarify the role of NSAb in NSAb-pos-CI and potentially help to identify a subgroup of patients with specific phenotypes, who could benefit from immunotherapies. The identification of such patients will allow their best clinical management.


Recruitment information / eligibility

Status Recruiting
Enrollment 300
Est. completion date June 30, 2026
Est. primary completion date June 30, 2026
Accepts healthy volunteers
Gender All
Age group 40 Years to 90 Years
Eligibility Inclusion Criteria: - both sexes - adult (aged between 40 and 90 years) - patients with a diagnosis of new-onset neurocognitive disorders (major and minor), as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, with onset within the previous 24 months Exclusion Criteria: - presence of a history of seizures within 4 weeks from onset.

Study Design


Related Conditions & MeSH terms


Locations

Country Name City State
Italy IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna
Italy Fondazione IRCCS Istituto Neurologico Carlo Besta Milano
Italy Istituto Auxologico Italiano IRCCS Milano

Sponsors (1)

Lead Sponsor Collaborator
Azienda Usl di Bologna

Country where clinical trial is conducted

Italy, 

References & Publications (12)

Bartels F, Stronisch T, Farmer K, Rentzsch K, Kiecker F, Finke C. Neuronal autoantibodies associated with cognitive impairment in melanoma patients. Ann Oncol. 2019 May 1;30(5):823-829. doi: 10.1093/annonc/mdz083. — View Citation

Brunkhorst R, Pfeilschifter W, Foerch C. Astroglial proteins as diagnostic markers of acute intracerebral hemorrhage-pathophysiological background and clinical findings. Transl Stroke Res. 2010 Dec;1(4):246-51. doi: 10.1007/s12975-010-0040-6. Epub 2010 Au — View Citation

Castillo-Gomez E, Oliveira B, Tapken D, Bertrand S, Klein-Schmidt C, Pan H, Zafeiriou P, Steiner J, Jurek B, Trippe R, Pruss H, Zimmermann WH, Bertrand D, Ehrenreich H, Hollmann M. All naturally occurring autoantibodies against the NMDA receptor subunit N — View Citation

Constantinescu R, Krysl D, Bergquist F, Andren K, Malmestrom C, Asztely F, Axelsson M, Menachem EB, Blennow K, Rosengren L, Zetterberg H. Cerebrospinal fluid markers of neuronal and glial cell damage to monitor disease activity and predict long-term outco — View Citation

Dubey D, Kothapalli N, McKeon A, Flanagan EP, Lennon VA, Klein CJ, Britton JW, So E, Boeve BF, Tillema JM, Sadjadi R, Pittock SJ. Predictors of neural-specific autoantibodies and immunotherapy response in patients with cognitive dysfunction. J Neuroimmuno — View Citation

Dubois B, Villain N, Frisoni GB, Rabinovici GD, Sabbagh M, Cappa S, Bejanin A, Bombois S, Epelbaum S, Teichmann M, Habert MO, Nordberg A, Blennow K, Galasko D, Stern Y, Rowe CC, Salloway S, Schneider LS, Cummings JL, Feldman HH. Clinical diagnosis of Alzh — View Citation

Flanagan EP, McKeon A, Lennon VA, Boeve BF, Trenerry MR, Tan KM, Drubach DA, Josephs KA, Britton JW, Mandrekar JN, Lowe V, Parisi JE, Pittock SJ. Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc. 2010 Oct;85(10 — View Citation

Giannoccaro MP, Cossins J, Sorland K, Fluge O, Vincent A. Searching for Serum Antibodies to Neuronal Proteins in Patients With Myalgic Encephalopathy/Chronic Fatigue Syndrome. Clin Ther. 2019 May;41(5):836-847. doi: 10.1016/j.clinthera.2019.04.001. Epub 2 — View Citation

Gibson LL, McKeever A, Cullen AE, Nicholson TR, Aarsland D, Zandi MS, Pollak TA. Neuronal surface autoantibodies in dementia: a systematic review and meta-analysis. J Neurol. 2021 Aug;268(8):2769-2779. doi: 10.1007/s00415-020-09825-0. Epub 2020 Apr 18. — View Citation

Pollak TA, Vincent A, Iyegbe C, Coutinho E, Jacobson L, Rujescu D, Stone J, Jezequel J, Rogemond V, Jamain S, Groc L, David A, Egerton A, Kahn RS, Honnorat J, Dazzan P, Leboyer M, McGuire P. Relationship Between Serum NMDA Receptor Antibodies and Response — View Citation

Wagner J, Witt JA, Helmstaedter C, Malter MP, Weber B, Elger CE. Automated volumetry of the mesiotemporal structures in antibody-associated limbic encephalitis. J Neurol Neurosurg Psychiatry. 2015 Jul;86(7):735-42. doi: 10.1136/jnnp-2014-307875. Epub 2014 — View Citation

Yeshokumar AK, Gordon-Lipkin E, Arenivas A, Cohen J, Venkatesan A, Saylor D, Probasco JC. Neurobehavioral outcomes in autoimmune encephalitis. J Neuroimmunol. 2017 Nov 15;312:8-14. doi: 10.1016/j.jneuroim.2017.08.010. Epub 2017 Aug 31. — View Citation

* Note: There are 12 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary frequency of antibodies against neuronal antigens NSAb frequency will be calculated by dividing the number of patients with NSAb with the total number of patients at baseline
Primary frequency of antibodies against neuronal antigens NSAb frequency will be calculated by dividing the number of patients with NSAb with the total number of patients 12 months (54 weeks)
Primary creation of a score that predicts the presence of NSAb Based on logistic regression models including the clinical, imaging and biomarkers data. The minimum and maximum score is to be defined on the bases of the analyses of the clinical data at 24 months milestone.An higher score is expected to be associated with the antibody presence. 24 months (108 weeks)
Secondary changes of neurodegeneration biomarkers comparison of blood biomarkers from baseline to one year follow up in seropositive versus seronegative patients. The blood biomarkers are: phosphorylated tau protein 181 (p-tau 181) (pg/mL), Neurofilament Light chain (NfL) (pg/mL), Glial Fibrillary Acidic Protein (GFAP) (pg/mL). at baseline
Secondary changes of neurodegeneration biomarkers comparison of blood biomarkers from baseline to one year follow up in seropositive versus seronegative patients. The blood biomarkers are: phosphorylated tau protein 181 (p-tau 181) (pg/mL), Neurofilament Light chain (NfL) (pg/mL), Glial Fibrillary Acidic Protein (GFAP) (pg/mL). 1 year (54 weeks)
Secondary changes of neuroanatomy comparison of Brain MRI from baseline to one year follow up in seropositive versus seronegative patients at baseline
Secondary changes of neuroanatomy comparison of Brain MRI from baseline to one year follow up in seropositive versus seronegative patients 1 year (54 weeks)
Secondary changes of inflammatory biomarkers comparison of inflammatory biomarkers from baseline to one year follow up in seropositive versus seronegative patients. The inflammatory biomarkers are: Interferon alpha (IFN alpha) (pg/mL), Interferon gamma (IFN gamma) (pg/mL), Interleukin-1 beta (IL-1 beta) (pg/mL), Interleukin-2 (IL-2) (pg/mL), Interleukin-4 (IL-4) (pg/mL), Interleukin-5 (IL-5) (pg/mL), Interleukin-6 (IL-6) (pg/mL), Interleukin-8 (IL-8) (pg/mL), Interleukin-17A (IL-17A) (pg/mL), Tumor necrosis factor alpha (TNF alpha) (pg/mL), Interferon gamma-induced protein 10 (IP-10) known as C-X-C motif chemokine 10(CXCL10) (pg/mL), Monocyte chemoattractant protein-1 (MCP-1) known as C-C motif chemokine ligand 2 (CCL2) (pg/mL). at baseline
Secondary changes of inflammatory biomarkers comparison of inflammatory biomarkers from baseline to one year follow up in seropositive versus seronegative patients. The inflammatory biomarkers are: Interferon alpha (IFN alpha) (pg/mL), Interferon gamma (IFN gamma) (pg/mL), Interleukin-1 beta (IL-1 beta) (pg/mL), Interleukin-2 (IL-2) (pg/mL), Interleukin-4 (IL-4) (pg/mL), Interleukin-5 (IL-5) (pg/mL), Interleukin-6 (IL-6) (pg/mL), Interleukin-8 (IL-8) (pg/mL), Interleukin-17A (IL-17A) (pg/mL), Tumor necrosis factor alpha (TNF alpha) (pg/mL), Interferon gamma-induced protein 10 (IP-10) known as C-X-C motif chemokine 10(CXCL10) (pg/mL), Monocyte chemoattractant protein-1 (MCP-1) known as C-C motif chemokine ligand 2 (CCL2) (pg/mL). 1 year (54 weeks)
Secondary changes of brain blood barrier biomarkers comparison of brain blood barrier biomarkers from baseline to one year follow up in seropositive versus seronegative patients. The biomarkers are: S100 calcium-binding protein B (S-100b) (pg/mL), Glial Fibrillary Acidic Protein (GFAP) (pg/mL). at baseline
Secondary changes of brain blood barrier biomarkers comparison of brain blood barrier biomarkers from baseline to one year follow up in seropositive versus seronegative patients. The biomarkers are: S100 calcium-binding protein B (S-100b) (pg/mL), Glial Fibrillary Acidic Protein (GFAP) (pg/mL). 1 year (54 weeks)
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