Blood plasma protein profiles of neuropsychiatric symptoms and related cognitive decline in older people

Rabl, Miriam; Clark, Christopher; Dayon, Loïc; Bowman, Gene L.; Popp, Julius

doi:10.1111/jnc.15715

Cited by 7 publications

(2 citation statements)

References 72 publications

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“…persistence of NPS over time and associated cognitive decline over 3 years. Interestingly, the associations seemed to be independent of the presence of AD pathology indicating pathways partially distinct from AD ( Rabl et al, 2022 ). Indeed, it appears only 30% of the proteins causative of neurodegenerative disease are implicated in psychiatric disorders ( Wingo et al, 2022 ).…”

Section: Molecular Alterations With Clinical Relevancementioning

confidence: 99%

The promise of multi-omics approaches to discover biological alterations with clinical relevance in Alzheimer’s disease

Clark

Rabl

Dayon

et al. 2022

Front. Aging Neurosci.

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Beyond the core features of Alzheimer’s disease (AD) pathology, i.e. amyloid pathology, tau-related neurodegeneration and microglia response, multiple other molecular alterations and pathway dysregulations have been observed in AD. Their inter-individual variations, complex interactions and relevance for clinical manifestation and disease progression remain poorly understood, however. Heterogeneity at both pathophysiological and clinical levels complicates diagnosis, prognosis, treatment and drug design and testing. High-throughput “omics” comprise unbiased and untargeted data-driven methods which allow the exploration of a wide spectrum of disease-related changes at different endophenotype levels without focussing a priori on specific molecular pathways or molecules. Crucially, new methodological and statistical advances now allow for the integrative analysis of data resulting from multiple and different omics methods. These multi-omics approaches offer the unique advantage of providing a more comprehensive characterisation of the AD endophenotype and to capture molecular signatures and interactions spanning various biological levels. These new insights can then help decipher disease mechanisms more deeply. In this review, we describe the different multi-omics tools and approaches currently available and how they have been applied in AD research so far. We discuss how multi-omics can be used to explore molecular alterations related to core features of the AD pathologies and how they interact with comorbid pathological alterations. We further discuss whether the identified pathophysiological changes are relevant for the clinical manifestation of AD, in terms of both cognitive impairment and neuropsychiatric symptoms, and for clinical disease progression over time. Finally, we address the opportunities for multi-omics approaches to help discover novel biomarkers for diagnosis and monitoring of relevant pathophysiological processes, along with personalised intervention strategies in AD.

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Section: Molecular Alterations With Clinical Relevancementioning

confidence: 99%

The promise of multi-omics approaches to discover biological alterations with clinical relevance in Alzheimer’s disease

Clark

Rabl

Dayon

et al. 2022

Front. Aging Neurosci.

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“…It is possible that elevated cortisol levels and cortisol/DHEAS ratio can reflect and/or contribute to more pronounced NPS in older people not only through worsening AD pathology and neurodegeneration [12], but possibly also through other mechanisms that are independent of the core AD pathology [17].…”

Section: Introductionmentioning

confidence: 99%

Persisting neuropsychiatric symptoms, Alzheimer’s disease, and cerebrospinal fluid cortisol and dehydroepiandrosterone sulfate

et al. 2022

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Introduction Neuropsychiatric symptoms are important treatment targets in the management of dementia and can be present at very early clinical stages of neurodegenerative diseases. Increased cortisol has been reported in Alzheimer’s disease (AD) and has been associated with faster cognitive decline. Elevated cortisol output has been observed in relation to perceived stress, depression, and anxiety. Dehydroepiandrosterone sulfate (DHEAS) has known anti-glucocorticoid effects and may counter the effects of cortisol. Objectives We aimed to examine whether CSF cortisol and DHEAS levels were associated with (1) neuropsychiatric symptoms at baseline, (2) changes in neuropsychiatric symptoms over 3 years, and (3) whether these associations were related to or independent of AD pathology. Methods One hundred and eighteen participants on a prospective study in a memory clinic setting, including patients with cognitive impairment (n = 78), i.e., mild cognitive impairment or mild dementia, and volunteers with normal cognition (n = 40), were included. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). CSF cortisol and DHEAS, as well as CSF AD biomarkers, were obtained at baseline. Neuropsychiatric symptoms were re-assessed at follow-up visits 18 and 36 months from baseline. We constructed linear regression models to examine the links between baseline neuropsychiatric symptoms, the presence of AD pathology as indicated by CSF biomarkers, and CSF cortisol and DHEAS. We used repeated-measures mixed ANCOVA models to examine the associations between the neuropsychiatric symptoms’ changes over time, baseline CSF cortisol and DHEAS, and AD pathology. Results Higher CSF cortisol was associated with higher NPI-Q severity scores at baseline after controlling for covariates including AD pathology status (B = 0.085 [0.027; 0.144], p = 0.027; r = 0.277). In particular, higher CSF cortisol was associated with higher baseline scores of depression/dysphoria, anxiety, and apathy/indifference. Elevated CSF cortisol was also associated with more marked increase in NPI-Q scores over time regardless of AD status (p = 0.036, η2 = 0.207), but this association was no longer significant after controlling for BMI and the use of psychotropic medications. CSF DHEAS was associated neither with NPI-Q scores at baseline nor with their change over time. Cortisol did not mediate the association between baseline NPI-Q and changes in clinical dementia rating sum of boxes over 36 months. Conclusion Higher CSF cortisol may reflect or contribute to more severe neuropsychiatric symptoms at baseline, as well as more pronounced worsening over 3 years, independently of the presence of AD pathology. Our findings also suggest that interventions targeting the HPA axis may be helpful to treat neuropsychiatric symptoms in patients with dementia.

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Modifiable lifestyle factors influencing psychiatric disorders mediated by plasma proteins: A systemic Mendelian randomization study

Chen,

Wang,

Teng

et al. 2024

Journal of Affective Disorders

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Blood plasma protein profiles of neuropsychiatric symptoms and related cognitive decline in older people

Cited by 7 publications

References 72 publications

The promise of multi-omics approaches to discover biological alterations with clinical relevance in Alzheimer’s disease

The promise of multi-omics approaches to discover biological alterations with clinical relevance in Alzheimer’s disease

Persisting neuropsychiatric symptoms, Alzheimer’s disease, and cerebrospinal fluid cortisol and dehydroepiandrosterone sulfate

Modifiable lifestyle factors influencing psychiatric disorders mediated by plasma proteins: A systemic Mendelian randomization study

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