Lipidomics profiling reveals distinct patterns of plasma sphingolipid alterations in Alzheimer's disease and vascular dementia.

BACKGROUND: Alzheimer's disease (AD) and vascular dementia (VaD) are two of the commonest causes of dementia in the elderly. Of the myriad biomolecules implicated in dementia pathogenesis, sphingolipids have attracted relatively scant research attention despite their known involvement in multiple pathophysiological processes. The potential utility of peripheral sphingolipids as biomarkers in dementia cohorts with high concomitance of cerebrovascular diseases is also unclear. METHODS: Using a lipidomics platform, we performed a case-control study of plasma sphingolipids in a prospectively assessed cohort of 526 participants (non-cognitively impaired, NCI = 93, cognitively impaired = 217, AD = 166, VaD = 50) using a lipidomics platform. RESULTS: Distinct patterns of sphingolipid alterations were found in AD and VaD, namely an upregulation of d18:1 species in AD compared to downregulation of d16:1 species in VaD. In particular, GM3 d18:1/16:0 and GM3 d18:1/24:1 showed the strongest positive associations with AD. Furthermore, evaluation of sphingolipids panels showed specific combinations with higher sensitivity and specificity for classification of AD (Cer d16:1/24:0. Cer d18:1/16:0, GM3 d16:1/22:0, GM3 d18:1/16:0, SM d16:1/22:0, HexCer d18:1/18:0) and VAD (Cer d16:1/24:0, Cer d18:1/16:0, Hex2Cer d16:1/16:0, HexCer d18:1/18:0, SM d16:1/16:0, SM d16:1/20:0, SM d18:2/22:0) compared to NCI. CONCLUSIONS: AD and VaD are associated with distinct changes of plasma sphingolipids, warranting further studies into underlying pathophysiological mechanisms and assessments of their potential utility as dementia biomarkers and therapeutic targets.

Mass Spectrometry Analysis of the Human Brain Sphingolipidome.

In recent decades, mass spectrometry-based lipidomics has provided a fertile environment for scientific investigations of biochemical and mechanistic processes in biological systems. Notably, this approach has been used to characterize physiological and pathological processes relevant to the central nervous system by identifying changes in the sphingolipid content in the brain, cerebral spinal fluid, and blood plasma. However, despite a preponderance of studies identifying correlations between specific lipids and disease progression, this powerful resource has not yet substantively translated into clinically useful diagnostic assays. Part of this gap may be explained by insufficient depth of the lipidomic profiles in many studies, by lab-to-lab inconsistencies in methodology, and a lack of absolute quantification. These issues limit the identification of specific molecular species and the harmonization of results across independent studies. In this chapter, we contextualize these issues with recent reports identifying correlations between brain lipids and neurological diseases, and we describe the workflow our group has optimized for analysis of the blood plasma sphingolipidome, adapted to the characterization of the human brain tissue.

Elevation of inactive cleaved annexin A1 in the neocortex is associated with amyloid, inflammatory and apoptotic markers in neurodegenerative dementias.

Inflammation is usually a tightly regulated process whose termination by mediators including Annexin A1 (AnxA1) results in the resolution of inflammatory responses. In neurodegenerative dementias, chronic neuroinflammation, along with accumulation of aggregated ß-amyloid (Aß) peptides and apoptosis, has long been recognized to be a pathological hallmark; but it is unclear whether a failure of inflammation resolution contributes to this pathophysiological process. In this study, we measured AnxA1 immunoreactivities in postmortem neocortex (Brodmann areas BA9 and BA40) of well characterized Alzheimer's disease (AD), Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) patients as well as aged controls. Inactive cleaved AnxA1 was found to be elevated in AD and DLB in BA40. Levels of cleaved AnxA1 also positively correlated with amyloidogenic brain Aß, anti-inflammatory markers such as IL10 and IL13, as well as with the pro-apoptotic marker cleaved caspase-3 in BA40. Our findings suggest that elevated cleaved AnxA1 in neurodegenerative dementias may reflect a failure of inflammation resolution in certain regions of the diseased brain, and also support a mechanistic link between AnxA1 and amyloid pathology, neuroinflammation and apoptosis.

Preclinical and Clinical Evidence for the Involvement of Sphingosine 1-Phosphate Signaling in the Pathophysiology of Vascular Cognitive Impairment.

Sphingosine 1-phosphates (S1Ps) are bioactive lipids that mediate a diverse range of effects through the activation of cognate receptors, S1P1-S1P5. Scrutiny of S1P-regulated pathways over the past three decades has identified important and occasionally counteracting functions in the brain and cerebrovascular system. For example, while S1P1 and S1P3 mediate proinflammatory effects on glial cells and directly promote endothelial cell barrier integrity, S1P2 is anti-inflammatory but disrupts barrier integrity. Cumulatively, there is significant preclinical evidence implicating critical roles for this pathway in regulating processes that drive cerebrovascular disease and vascular dementia, both being part of the continuum of vascular cognitive impairment (VCI). This is supported by clinical studies that have identified correlations between alterations of S1P and cognitive deficits. We review studies which proposed and evaluated potential mechanisms by which such alterations contribute to pathological S1P signaling that leads to VCI-associated chronic neuroinflammation and neurodegeneration. Notably, S1P receptors have divergent but overlapping expression patterns and demonstrate complex interactions. Therefore, the net effect produced by S1P represents the cumulative contributions of S1P receptors acting additively, synergistically, or antagonistically on the neural, vascular, and immune cells of the brain. Ultimately, an optimized therapeutic strategy that targets S1P signaling will have to consider these complex interactions.

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

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.

Enablers and Barriers of a Cross-Cultural Geriatric Education Distance Training Programme: The Singapore-Uganda Experience.

BACKGROUND: By 2050, 80% of the world's older population will reside in developing countries. There is a need for culturally appropriate training programs to increase awareness of eldercare issues, promote knowledge of how to better allocate resources to geriatric services, and promulgate elder-friendly policies. A monthly distance geriatric education programme between a public hospital in Singapore and health institute in Uganda was implemented. This study explored the enablers and barriers to the delivery of culturally appropriate geriatric education programmes via a videoconferencing platform. METHODS: We conducted 12 in-depth interviews with six teachers from Singapore and six learners from Uganda. The interviews were audio-recorded, transcribed and analyzed using an inductive thematic approach to analysis with the aid of the NVivo software. RESULTS: Enablers included inter-personal real-time interactions between teachers and learners whereas misaligned perceptions of cross-cultural differences between Singaporean teachers and Ugandan learners were a barrier. Rapport building, teacher motivation and institutional support were perceived to contribute to the programme's sustainability. Overall, Ugandan learners perceived that the training improved knowledge, skills, attitude and practice of geriatric care. Participants suggested that future initiatives consider aligning cross-cultural perceptions between partners, conducting a training needs analysis, exploring complementary modes of information dissemination, and allotting time for more interaction, thereby reinforcing mutual sharing. Adequate publicity and appropriate incentivisation may also better sustain the programme. CONCLUSIONS: Our findings suggest that cross-cultural training via a videoconferencing platform was feasible. Our results inform planners of future distance educational programmes of how to improve standards of cross-cultural competency and forge promising international partnerships.

Evaluation of clinical frailty screening in geriatric acute care.

BACKGROUND: While frailty status is an attractive risk stratification tool, the evaluation of frailty in acute care can be challenging as some inpatients are unable to complete performance-based tests as part of frailty assessment and some tools may lack discriminative ability and categorize majority of cohorts as "frail". In this study, we evaluated the feasibility of frailty screening with the simple clinical frailty scale (CFS) by different clinicians, and its association with mortality and rehospitalization in a geriatric acute care setting. METHODS: This study took place in Geriatric Medicine Department of a General Hospital in Singapore. We analysed records of 314 inpatients aged 70 years and older. At baseline, premorbid frailty was assessed using the CFS of the Canadian Study on Health and Aging. Demographic characteristics and other variables were retrieved from their medical records. Primary outcomes were mortality and rehospitalization during the 6-month follow-up. Survival analysis was used to compare the time to death and rehospitalization among CFS categories (1-4: nonfrail, 5-6: mild-moderate frail, and 7-8: severe frail). RESULTS: CFS showed a high inter-rater reliability when used by different clinicians. In the Cox proportional hazard model controlling for age, gender, Charlson comorbidity index, modified severity of illness index, and discharge placements, severe frailty determined by CFS (HR = 2.09, 95% CI = 1.01-4.33, P = 0.047) and CFS scores (HR = 1.27, 95% CI = 1.05-1.53, P = 0.012) were significantly associated with higher mortality until 6-month postdischarge, but not rehospitalization. CONCLUSION: Frailty status determined by CFS adds to disease severity and comorbidity in predicting short-term mortality but not rehospitalization in older inpatients who received geriatric acute care in our setting. CFS is reliable and has the potential to be incorporated into routine screening to better identify, communicate, and address frailty in the acute settings.

Mapping modified Mini-Mental State Examination (MMSE) scores to dementia stages in a multi-ethnic Asian population.

ABSTRACTThe MMSE is used to screen for cognitive impairment and estimate dementia severity. In clinical settings, conventional cut-off scores have been used to distinguish between dementia stages. However, these scores have not been validated for different populations. This study maps scores from the modified version of the MMSE to dementia stages delineated by the Diagnostic and Statistical Manual of Mental Disorders-3rd revised edition (DSM-III-R), the Clinical Dementia Rating (CDR) and Functional Assessment Staging Test (FAST). We used cross-sectional data from a tertiary hospital memory clinic. Subjects were stratified into "primary education and below" (PE) or "secondary education and above" (SE). Receiving operating characteristic (ROC) analyses and Cohen's κ were performed to determine MMSE cut-off scores for dementia stages. Our derived cut-off scores were lower compared to the conventional scores. Scores also differed between subjects of different education levels. MMSE cut-off scores were 19, 15, and 9 for CDR stages 1, 2, and 3 respectively in PE subjects, and 23, 17, and 10 for SE subjects. Cut-off scores were comparable for staging by DSM-III-R Criteria and FAST. There is a need for locally derived stage-specific MMSE cut-off scores for the Asian population adjusted for education.