Immunomodulatory sphingosine-1-phosphates as plasma biomarkers of Alzheimer’s disease and vascular cognitive impairment

Abstract Background There has been ongoing research impetus to uncover novel blood-based diagnostic and prognostic biomarkers for Alzheimer’s disease (AD), vascular dementia (VaD), and related cerebrovascular disease (CEVD)-associated conditions within the spectrum of vascular cognitive impairment (VCI). Sphingosine-1-phosphates (S1Ps) are signaling lipids which act on the S1PR family of cognate G-protein-coupled receptors and have been shown to modulate neuroinflammation, a process known to be involved in both neurodegenerative and cerebrovascular diseases. However, the status of peripheral S1P in AD and VCI is at present unclear. Methods We obtained baseline bloods from individuals recruited into an ongoing longitudinal cohort study who had normal cognition (N = 80); cognitive impairment, no dementia (N = 160); AD (N = 113); or VaD (N = 31), along with neuroimaging assessments of cerebrovascular diseases. Plasma samples were processed for the measurements of major S1P species: d16:1, d17:1, d18:0, and d18:1, along with pro-inflammatory cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF). Furthermore, in vitro effects of S1Ps on cytokine expression were also studied in an astrocytoma cell line and in rodent primary astrocytes. Results Of the S1Ps species measured, only d16:1 S1P was significantly reduced in the plasma of VaD, but not AD, patients, while the d18:1 to d16:1 ratios were increased in all cognitive subgroups (CIND, AD, and VaD). Furthermore, d18:1 to d16:1 ratios correlated with levels of IL-6, IL-8, and TNF. In both primary astrocytes and an astroglial cell line, treatment with d16:1 or d18:1 S1P resulted in the upregulation of mRNA transcripts of pro-inflammatory cytokines, with d18:1 showing a stronger effect than d16:1. Interestingly, co-treatment assays showed that the addition of d16:1 reduced the extent of d18:1-mediated gene expression, indicating that d16:1 may function to “fine-tune” the pro-inflammatory effects of d18:1. Conclusion Taken together, our data suggest that plasma d16:1 S1P may be useful as a diagnostic marker for VCI, while the d18:1 to d16:1 S1P ratio is an index of dysregulated S1P-mediated immunomodulation leading to chronic inflammation-associated neurodegeneration and cerebrovascular damage.

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Biomarkers of vascular cognitive impairment

CARDIOVASCULAR THERAPY AND PREVENTION ◽

10.15829/1728-8800-2021-2677 ◽

2021 ◽

Vol 20 (3) ◽

pp. 2677

Author(s):

O. V. Zimnitskaya ◽

E. Yu. Mozheyko ◽

M. M. Petrova

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Differential Diagnosis ◽

Cognitive Impairment ◽

Cognitive Dysfunction ◽

Web Of Science ◽

Vascular Cognitive Impairment ◽

Cerebrovascular Diseases ◽

Adequate Treatment ◽

Genetic Biomarkers

There is currently no approved list of vascular cognitive impairment biomarkers. The main problem for the practitioner in identifying cognitive impairment in patients is the differential diagnosis of Alzheimer's disease, vascular cognitive impairment, and other diseases, which are much less common. Vascular cognitive impairment includes post-stroke dementia, cognitive dysfunction in cardio-and cerebrovascular diseases. Without etiology identification, it is impossible to prescribe adequate treatment. Another challenge is identifying cognitive impairment before dementia develops. This literature review is devoted to the search and critical analysis of candidates for biomarkers of vascular cognitive impairment and the establishment of markers of moderate cognitive dysfunction. The papers were searched for in the Web of Science and PubMed databases. A list of cerebrospinal fluid, plasma, serum and genetic biomarkers was made, allowing for differential diagnosis between vascular impairment and Alzheimer's disease. The markers of moderate cognitive dysfunction, which make it possible to identify cognitive impairment at the pre-dementia stage, were also identified.

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Plasma osteopontin as a biomarker of Alzheimer’s disease and vascular cognitive impairment

Scientific Reports ◽

10.1038/s41598-021-83601-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yuek Ling Chai ◽

Joyce R. Chong ◽

Ainiah R. Raquib ◽

Xin Xu ◽

Saima Hilal ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Inflammatory Cytokines ◽

Inflammatory Marker ◽

Vascular Diseases ◽

The Elderly ◽

Vascular Cognitive Impairment ◽

Cross Sectional Study ◽

Cross Sectional

AbstractCerebrovascular disease (CeVD) and neurodegenerative dementia such as Alzheimer’s disease (AD) are frequently associated comorbidities in the elderly, sharing common risk factors and pathophysiological mechanisms including neuroinflammation. Osteopontin (OPN) is an inflammatory marker found upregulated in vascular diseases as well as in AD. However, its involvement in vascular dementia (VaD) and pre-dementia stages, namely cognitive impairment no dementia (CIND), both of which fall under the spectrum of vascular cognitive impairment (VCI), has yet to be examined. Its correlations with inflammatory cytokines in cognitive impairment also await investigation. 80 subjects with no cognitive impairment (NCI), 160 with CIND and 144 with dementia were included in a cross-sectional study on a Singapore-based memory clinic cohort. All subjects underwent comprehensive clinical, neuropsychological and brain neuroimaging assessments, together with clinical diagnoses based on established criteria. Blood samples were collected and OPN as well as inflammatory cytokines interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF) were measured using immunoassays. Multivariate regression analyses showed significant associations between increased OPN and VCI groups, namely CIND with CeVD, AD with CeVD and VaD. Interestingly, higher OPN was also significantly associated with AD even in the absence of CeVD. We further showed that increased OPN significantly associated with neuroimaging markers of CeVD and neurodegeneration, including cortical infarcts, lacunes, white matter hyperintensities and brain atrophy. OPN also correlated with elevated levels of IL-6, IL-8 and TNF. Our findings suggest that OPN may play a role in both VCI and neurodegenerative dementias. Further longitudinal analyses are needed to assess the prognostic utility of OPN in disease prediction and monitoring.

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Plasma Osteopontin as a Biomarker of Alzheimer’s Disease and Vascular Cognitive Impairment: A Case-Control Study

10.21203/rs.3.rs-89257/v1 ◽

2020 ◽

Author(s):

Yuek Ling Chai ◽

Joyce R Chong ◽

Ainiah R Raquib ◽

Xin Xu ◽

Saima Hilal ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Inflammatory Cytokines ◽

Inflammatory Marker ◽

Vascular Diseases ◽

The Elderly ◽

Vascular Cognitive Impairment ◽

Cross Sectional Study ◽

Cross Sectional

Abstract Background: Cerebrovascular disease (CeVD) and neurodegenerative dementia such as Alzheimer’s disease (AD) are frequently associated comorbidities in the elderly, sharing common risk factors and pathophysiological mechanisms including neuroinflammation. Osteopontin (OPN) is an inflammatory marker found upregulated in vascular diseases as well as in AD. However, its involvement in vascular dementia (VaD) and pre-dementia stages, namely cognitive impairment no dementia (CIND), both of which fall under the spectrum of vascular cognitive impairment (VCI) has yet to be examined. Its correlations with inflammatory cytokines in cognitive impairment also await investigation. Methods: 80 subjects with no cognitive impairment (NCI), 160 with CIND and 144 with dementia were included in a cross-sectional study on a Singapore-based memory clinic cohort. All subjects underwent comprehensive clinical, neuropsychological and brain neuroimaging assessments, together with clinical diagnoses based on established criteria. Blood samples were collected and OPN as well as inflammatory cytokines interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF) were measured using immunoassays. Results: Multivariate regression analyses showed significant associations between increased OPN and VCI groups, namely CIND with CeVD, AD with CeVD and VaD. Interestingly, higher OPN was also significantly associated with AD even in the absence of CeVD. We further showed that increased OPN significantly associated with neuroimaging markers of CeVD and neurodegeneration, including cortical infarcts, lacunes, white matter hyperintensities and brain atrophy. OPN also correlated with elevated levels of IL-6, IL-8 and TNF. Conclusions: Our findings suggest that OPN may play a role in both VCI and neurodegenerative dementias. Further longitudinal analyses are needed to assess the prognostic utility of OPN in disease prediction and monitoring.

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The Brief Memory and Executive Test (BMET): A cognitive screening tool to detect and differentiate vascular cognitive impairment and Alzheimer's disease

International Journal of Geriatric Psychiatry ◽

10.1002/gps.4787 ◽

2017 ◽

Vol 33 (2) ◽

pp. e273-e279 ◽

Cited By ~ 3

Author(s):

Matthew J. Hollocks ◽

Rebecca L. Brookes ◽

Robin G. Morris ◽

Hugh S. Markus

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Screening Tool ◽

Vascular Cognitive Impairment ◽

Cognitive Screening

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Hemodynamics in Alzheimer’s Disease and Vascular Cognitive Impairment and Dementia

Vascular Disease, Alzheimer's Disease, and Mild Cognitive Impairment ◽

10.1093/oso/9780190634230.003.0014 ◽

2020 ◽

pp. 302-330

Author(s):

Francis Cambronero ◽

Angela L. Jefferson

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Cerebrovascular Disease ◽

Vascular System ◽

Clinical Symptoms ◽

Vascular Dysfunction ◽

Critical Role ◽

Vascular Cognitive Impairment ◽

Aging Adults

Hemodynamic impairment is a prominent feature in aging, vascular cognitive impairment and dementia, and Alzheimer’s disease, including patterned changes in cerebral blood flow (CBF) that can be detected prior to concomitant pathologies. These CBF abnormalities drive vascular dysfunction through a variety of biological pathways and ultimately contribute to cerebrovascular disease associated with cognitive impairment. Importantly, the co-existence of cerebrovascular disease and Alzheimer’s disease is exceedingly common and worsens the progression of clinical symptoms, likely through accelerating neurotoxic protein deposition and the loss of cerebrovascular integrity. Emerging evidence further suggests that the brain may be more susceptible to subclinical cardiovascular dysfunction in aging adults, particularly since the accumulation of cardiovascular risk factors over the lifespan creates a more vulnerable vascular system. Although age-associated CBF dysregulation has varied and complex origins, it undoubtedly serves a critical role in the early progression of neurodegenerative disease and may help explain the considerable overlap between the most common clinical dementias.

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Linguistic abilities in major vascular cognitive impairment: a comparative study with Alzheimer’s disease

Acta Neurologica Belgica ◽

10.1007/s13760-018-0977-x ◽

2018 ◽

Vol 118 (3) ◽

pp. 465-473 ◽

Cited By ~ 1

Author(s):

Maria Isabel D’Avila Freitas ◽

Claudia S. Porto ◽

Maira O. Oliveira ◽

Sonia M. D. Brucki ◽

Leticia L. Mansur ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Comparative Study ◽

Vascular Cognitive Impairment

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Alzheimer's disease and periodontitis - an elusive link

Revista da Associação Médica Brasileira ◽

10.1590/1806-9282.60.02.015 ◽

2014 ◽

Vol 60 (2) ◽

pp. 173-180 ◽

Cited By ~ 16

Author(s):

Abhijit N. Gurav

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Inflammatory Cytokines ◽

Critical Role ◽

Anaerobic Bacteria ◽

Systemic Infection ◽

Low Grade ◽

Inflammatory Status ◽

Pro Inflammatory Cytokines

Alzheimer's disease is the preeminent cause and commonest form of dementia. It is clinically characterized by a progressive descent in the cognitive function, which commences with deterioration in memory. The exact etiology and pathophysiologic mechanism of Alzheimer's disease is still not fully understood. However it is hypothesized that, neuroinflammation plays a critical role in the pathogenesis of Alzheimer's disease. Alzheimer's disease is marked by salient inflammatory features, characterized by microglial activation and escalation in the levels of pro-inflammatory cytokines in the affected regions. Studies have suggested a probable role of systemic infection conducing to inflammatory status of the central nervous system. Periodontitis is common oral infection affiliated with gram negative, anaerobic bacteria, capable of orchestrating localized and systemic infections in the subject. Periodontitis is known to elicit a "low grade systemic inflammation" by release of pro-inflammatory cytokines into systemic circulation. This review elucidates the possible role of periodontitis in exacerbating Alzheimer's disease. Periodontitis may bear the potential to affect the onset and progression of Alzheimer's disease. Periodontitis shares the two important features of Alzheimer's disease namely oxidative damage and inflammation, which are exhibited in the brain pathology of Alzheimer's disease. Periodontitis can be treated and hence it is a modifiable risk factor for Alzheimer's disease.

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