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. 2024 Oct;31(10):e16388.
doi: 10.1111/ene.16388. Epub 2024 Jul 1.

Association of elevated cerebrospinal fluid levels of the longevity protein α-Klotho with a delayed onset of cognitive impairment in Parkinson's disease patients

Milan Zimmermann  1   2 , Madeleine Fandrich  3 , Meike Jakobi  3 , Benjamin Röben  1   2 , Isabel Wurster  1   2 , Stefanie Lerche  1   2 , Claudia Schulte  1   2 , Shahrzad Zimmermann  1 , Christian Deuschle  1   2 , Nicole Schneiderhan-Marra  3 , Thomas Gasser  1   2 , Kathrin Brockmann  1   2
Affiliations

Association of elevated cerebrospinal fluid levels of the longevity protein α-Klotho with a delayed onset of cognitive impairment in Parkinson's disease patients

Milan Zimmermann et al. Eur J Neurol. 2024 Oct.

Abstract

Background and purpose: Parkinson's disease (PD) is an age-related condition characterized by substantial phenotypic variability. Consequently, pathways and proteins involved in biological aging, such as the central aging pathway comprising insulin-like growth factor 1-α-Klotho-sirtuin 1-forkhead box O3-peroxisome proliferator-activated receptor γ, may potentially influence disease progression.

Methods: Cerebrospinal fluid (CSF) levels of α-Klotho in 471 PD patients were examined. Of the 471 patients, 96 carried a GBA1 variant (PD GBA1), whilst the 375 non-carriers were classified as PD wild-type (PD WT). Each patient was stratified into a CSF α-Klotho tertile group based on the individual level. Kaplan-Meier survival curves and Cox regression analysis stratified by tertile groups were conducted. These longitudinal data were available for 255 patients. Follow-up times reached from 8.4 to 12.4 years. The stratification into PD WT and PD GBA1 was undertaken to evaluate potential continuum patterns, particularly in relation to CSF levels.

Results: Higher CSF levels of α-Klotho were associated with a significant later onset of cognitive impairment. Elevated levels of α-Klotho in CSF were linked to higher Montreal Cognitive Assessment scores in male PD patients with GBA1 mutations.

Conclusions: Our results indicate that higher CSF levels of α-Klotho are associated with a delayed cognitive decline in PD. Notably, this correlation is more prominently observed in PD patients with GBA1 mutations, potentially reflecting the accelerated biological aging profile characteristic of individuals harboring GBA1 variants.

Keywords: Parkinson's disease; aging; neurodegeneration; neurodegenerative diseases; α‐Klotho.

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Conflict of interest statement

No conflicts of interest are reported for any of the authors in relation to the content of this paper. Dr Kathrin Brockmann received Research Grants from the Michael J. Fox Foundation for Parkinson's Research (LRRK2 Kinase Activity, Influence of Inflammatory Profiles on PD Phenotype and Progression, Prevent Dementia in GBA1‐associated PD), from the University of Tuebingen (Endophenotyping of GBA1‐PD), from the German Society for Parkinson DPG, from the Health Forum Baden Wuerttemberg (Predictive Diagnostic of Immune‐associated Diseases for Personalized Medicine, AZ 35‐4223.10/8), from the Else Kröner Fresenius Stiftung (ClinBrain) and from the German Research Foundation DFG (CORO‐TREND). She serves on advisory boards for F. Hoffmann‐La Roche Ltd and VanqaBio. She received speaker honoraria from Abbvie, Lundbeck, UCB and Zambon. Professor Dr Thomas Gasser serves on the editorial board of the Journal of Parkinson's Disease. He holds a patent re KASPP (LRRK2) gene, its production and use for the detection and treatment of neurodegenerative diseases. Professor Gasser has received speaker's honoraria from UCB Pharma, Novartis, Sanofi and MedUpdate. He has received consulting fees from Bayer AG, BlueRock Therapeutics and Biogen. He is Chairman of the Scientific Advisory Board of the Joint Programming for Neurodegenerative Diseases program, funded by the European Commission. He has received grant support from the German Research Foundation (DFG), the German Federal Ministry of Education and Research (BMBF), the Ministry for Science, Research and Art Baden‐Württemberg (MWK), the European Commission, the Helmholtz Association and the Michael J. Fox Foundation. Dr Benjamin Röben has received a research grant from the University of Tuebingen (Clinician Scientist; Project‐Nr. 480‐0‐0). Dr Nicole Schneiderhan‐Marra has received funding from the State Ministry of Baden‐Württemberg for Economic Affairs, Labour and Tourism (Predictive Diagnostic of Immune‐associated Diseases for Personalized Medicine, AZ 35‐4223.10/8). Dr Isabel Wurster receives funding from the Michael J. Fox Foundation as an Edmond J. Safra Fellow in Movement Disorders. Dr Milan Zimmermann has received a research grant from the University of Tuebingen (Clinician Scientist; Project‐Nr. 481‐0‐0) and the remaining authors have nothing to disclose.

Figures

FIGURE 1
FIGURE 1
α‐Klotho counteracts the phosphorylation of Forkhead box O3 (FOXO3a), amongst others, via phosphoinositide 3‐kinase/protein kinase B (PI3K/AKT) inhibition, preventing the dislocation of this central transcription factor from the nucleus and thus leading to increased expression of antioxidative enzymes like superoxide dismutase II (SODII) and human catalase (CAT) via activation of peroxisome proliferator‐activated receptor γ (PPARγ). Possible effects are a lower production of interleukins and reactive oxygen species, an increase in mitochondrial biogenesis and autophagy and thus an increase in life expectancy [16]. Created with BioRender.com.
FIGURE 2
FIGURE 2
Kaplan–Meier survival curves and Cox regression analysis for the time interval (in years) until 50% of the Parkinson's disease patients reached the milestone cognitive impairment (MoCA ≤25) in the PD total cohort (a), the PD wild‐type (WT) (b) and PD GBA1 (c), stratified by tertiles of CSF α‐Klotho levels. Categories: lowest tertile of α‐Klotho CSF levels; mid tertile of α‐Klotho levels; highest tertile of α‐Klotho levels. p values <0.05 are highlighted in bold.
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