Serum Metabolomic and Lipidomic Profiling Reveals Novel Biomarkers of Efficacy for Benfotiamine in Alzheimer’s Disease

Serum metabolomics and lipidomics are powerful approaches for discovering unique biomarkers in various diseases and associated therapeutics and for revealing metabolic mechanisms of both. Treatment with Benfotiamine (BFT), a thiamine prodrug, for one year produced encouraging results for patients with mild cognitive impairment and mild Alzheimer’s disease (AD). In this study, a parallel metabolomics and lipidomics approach was applied for the first exploratory investigation on the serum metabolome and lipidome of patients treated with BFT. A total of 315 unique metabolites and 417 lipids species were confidently identified and relatively quantified. Rigorous statistical analyses revealed significant differences between the placebo and BFT treatment groups in 25 metabolites, including thiamine, tyrosine, tryptophan, lysine, and 22 lipid species, mostly belonging to phosphatidylcholines. Additionally, 10 of 11 metabolites and 14 of 15 lipid species reported in previous literature to follow AD progression changed in the opposite direction to those reported to reflect AD progression. Enrichment and pathway analyses show that significantly altered metabolites by BFT are involved in glucose metabolism and biosynthesis of aromatic amino acids. Our study discovered that multiple novel biomarkers and multiple mechanisms that may underlie the benefit of BFT are potential therapeutic targets in AD and should be validated in studies with larger sample sizes.

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Plasma contact factors as novel biomarkers for diagnosing Alzheimer’s disease

Biomarker Research ◽

10.1186/s40364-020-00258-5 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Jung Eun Park ◽

Do Sung Lim ◽

Yeong Hee Cho ◽

Kyu Yeong Choi ◽

Jang Jae Lee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Clinical Stage ◽

Area Under The Curve ◽

Contact System ◽

Plasma Diagnostic ◽

Vascular Abnormalities ◽

Prodromal Ad ◽

Novel Biomarkers

Abstract Background Alzheimer’s disease (AD) is the most common cause of dementia and most of AD patients suffer from vascular abnormalities and neuroinflammation. There is an urgent need to develop novel blood biomarkers capable of diagnosing Alzheimer’s disease (AD) at very early stage. This study was performed to find out new accurate plasma diagnostic biomarkers for AD by investigating a direct relationship between plasma contact system and AD. Methods A total 101 of human CSF and plasma samples from normal and AD patients were analyzed. The contact factor activities in plasma were measured with the corresponding specific peptide substrates. Results The activities of contact factors (FXIIa, FXIa, plasma kallikrein) and FXa clearly increased and statistically correlated as AD progresses. We present here, for the first time, the FXIIa cut-off scores to as: > 26.3 U/ml for prodromal AD [area under the curve (AUC) = 0.783, p < 0.001] and > 27.2 U/ml for AD dementia (AUC = 0.906, p < 0.001). We also describe the cut-off scores from the ratios of CSF Aβ1–42 versus the contact factors. Of these, the representative ratio cut-off scores of Aβ1–42/FXIIa were to be: < 33.8 for prodromal AD (AUC = 0.965, p < 0.001) and < 27.44 for AD dementia (AUC = 1.0, p < 0.001). Conclusion The activation of plasma contact system is closely associated with clinical stage of AD, and FXIIa activity as well as the cut-off scores of CSF Aβ1–42/FXIIa can be used as novel accurate diagnostic AD biomarkers.

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F1-01-03: Gene-wide and pathway analyses identify new susceptibility genes and pathways related to Alzheimer's disease

Alzheimer s & Dementia ◽

10.1016/j.jalz.2013.04.042 ◽

2013 ◽

Vol 9 ◽

pp. P123-P123

Author(s):

Valentina Moskvina

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Susceptibility Genes ◽

Pathway Analyses

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Novel biomarkers in Alzheimer’s disease using high resolution proteomics and metabolomics: miRNAS, proteins and metabolites

Critical Reviews in Clinical Laboratory Sciences ◽

10.1080/10408363.2020.1833298 ◽

2020 ◽

pp. 1-13

Author(s):

Diana Navas-Carrillo ◽

José Miguel Rivera-Caravaca ◽

Arturo Sampedro-Andrada ◽

Esteban Orenes-Piñero

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Resolution ◽

Novel Biomarkers

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Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms222212256 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12256

Author(s):

Estibaliz González de San Román ◽

Alberto Llorente-Ovejero ◽

Jonatan Martínez-Gardeazabal ◽

Marta Moreno-Rodríguez ◽

Lydia Giménez-Llort ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fatty Acid ◽

Motor Cortex ◽

Mouse Model ◽

Transgenic Mouse ◽

Neurodegenerative Disorder ◽

Transgenic Mouse Model ◽

Lipid Species ◽

Triple Transgenic Mouse

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in aging populations. Recently, the regulation of neurolipid-mediated signaling and cerebral lipid species was shown in AD patients. The triple transgenic mouse model (3xTg-AD), harboring βAPPSwe, PS1M146V, and tauP301L transgenes, mimics many critical aspects of AD neuropathology and progressively develops neuropathological markers. Thus, in the present study, 3xTg-AD mice have been used to test the involvement of the neurolipid-based signaling by endocannabinoids (eCB), lysophosphatidic acid (LPA), and sphingosine 1-phosphate (S1P) in relation to the lipid deregulation. [35S]GTPγS autoradiography was used in the presence of specific agonists WIN55,212-2, LPA and CYM5442, to measure the activity mediated by CB1, LPA1, and S1P1 Gi/0 coupled receptors, respectively. Consecutive slides were used to analyze the relative intensities of multiple lipid species by MALDI Mass spectrometry imaging (MSI) with microscopic anatomical resolution. The quantitative analysis of the astrocyte population was performed by immunohistochemistry. CB1 receptor activity was decreased in the amygdala and motor cortex of 3xTg-AD mice, but LPA1 activity was increased in the corpus callosum, motor cortex, hippocampal CA1 area, and striatum. Conversely, S1P1 activity was reduced in hippocampal areas. Moreover, the observed modifications on PC, PA, SM, and PI intensities in different brain areas depend on their fatty acid composition, including decrease of polyunsaturated fatty acid (PUFA) phospholipids and increase of species containing saturated fatty acids (SFA). The regulation of some lipid species in specific brain regions together with the modulation of the eCB, LPA, and S1P signaling in 3xTg-AD mice indicate a neuroprotective adaptation to improve neurotransmission, relieve the myelination dysfunction, and to attenuate astrocyte-mediated neuroinflammation. These results could contribute to identify new therapeutic strategies based on the regulation of the lipid signaling in familial AD patients.

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Anticholinergics and Benzodiazepines on Cognitive Impairment among Elderly with Alzheimer’s Disease: a One year Follow-Up Study

10.21203/rs.2.17956/v1 ◽

2019 ◽

Author(s):

Rewadee Jenraumjit ◽

Surarong Chinwong ◽

Dujrudee Chinwong ◽

Tipaporn Kanjanarach ◽

Thanat Kshetradat ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Psychological Symptoms ◽

Esterase Inhibitors ◽

One Year ◽

State Examination ◽

Harmful Effects

Abstract Objective Age-associated decline in central cholinergic activity makes older adults susceptible to harmful effects of anticholinergics (ACs). Evidence exists of an association between effects of AC medications on cognition. This retrospective cohort study examines how ACs affect cognition among older adults with Alzheimer’s disease (AD) who received acetylcholine esterase inhibitors (AChEIs) over the course of 12 months. Results A total of 133 (80% women, mean age 78.38 years, SD 7.4) were recruited. No difference in sex, age and comorbid diseases was observed between participants who took ACs, Benzodiazepines (BZDs) and AChEIs. The most common prescribed ACs was quetiapine, being used for behavioral and psychological symptoms (BPSD). Multilevel analysis showed that the change of mental state examination scores were significantly predicted in the group using ACs (t (169), -2.52, p = .020) but not with the groups using BZD (t (162), 0.84, p = .440). Evidence showed that older adults with Alzheimer’s disease and exposed to ACs exhibited lower global cognitive scores than those without AC exposure. Using ACs could be a trade-off between controlling BPSD and aggravating cognitive impairment. Highlighting the awareness of the potential anticholinergic effect is important and may be the best policy.

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VANUTIDE CRIDIFICAR (ACC-001) AND QS-21 ADJUVANT IN INDIVIDUALS WITH EARLY ALZHEIMER’S DISEASE: AMYLOID IMAGING POSITRON EMISSION TOMOGRAPHY AND SAFETY RESULTS FROM A PHASE 2 STUDY

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2016.91 ◽

2016 ◽

pp. 1-10

Author(s):

C.H. van Dyck ◽

C. Sadowsky ◽

G. Le Prince Leterme ◽

K. Booth ◽

Y. Peng ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Positron Emission Tomography ◽

Amyloid Beta ◽

Standard Uptake Value ◽

Emission Tomography ◽

Amyloid Burden ◽

Treatment Groups ◽

Positron Emission ◽

Early Alzheimer’S Disease

BACKGROUNDd: ACC-001 is an investigational therapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer’s disease. OBJECTIVES: To evaluate safety, immunogenicity, impact on brain amyloid, and other exploratory endpoints in participants receiving ACC-001. DESIGN: Randomized, phase 2, interventional study. Trial registration: Clinicaltrials.gov ID NCT01227564. PARTICIPANTS: Individuals with early Alzheimer’s disease (Mini-Mental State Examination scores ≥25, a global Clinical Dementia Rating of 0.5, and evidence of elevated baseline brain amyloid burden). Intervention: Participants were randomized to ACC-001 3 µg or 10 µg with QS-21 adjuvant (50 µg), or placebo. MEASUREMENTS: The primary endpoint was change in brain amyloid burden by 18F-florbetapir positron emission tomography in composite cortical standard uptake value ratio. RESULTS: A total of 63 participants were randomized and 51 completed the study. At week 104, no significant differences were observed in 18F-florbetapir positron emission tomography composite cortical standard uptake value ratio between either ACC-001 dose compared with placebo. In both ACC-001 + QS-21 treatment groups, following the initial immunization, the anti-amyloid-beta geometric mean titers increased after each subsequent vaccination and then declined, with less apparent decline after the later compared with earlier immunizations. The majority of treatment-emergent adverse events in the ACC-001 + QS-21 groups were injection site reactions, which occurred at a greater rate in active treatment groups than in the placebo group. No amyloid-related imaging abnormalities of edema or effusion were reported. CONCLUSION: No statistically significant differences were observed between groups in the change from baseline brain amyloid burden despite apparently robust systemically measured anti-amyloid-beta antibody response at both dose levels. Insufficient antibody titers, poor quality immune response, short duration of treatment, or small sample size may have resulted in these findings. The safety and tolerability profile was acceptable.

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Suicide risk within one year of cognitive impairment diagnosis in older adults: a nationwide retrospective cohort study

10.21203/rs.2.19129/v1 ◽

2019 ◽

Author(s):

Jae Woo Choi ◽

Kang Soo Lee ◽

Euna Han

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mental Disorders ◽

Suicide Risk ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Models ◽

One Year

Abstract Background This study aims to investigate suicide risk within one year of receiving a diagnosis of cognitive impairment in older adults without mental disorders. Methods This study used National Health Insurance Service-Senior Cohort data on older adults with newly diagnosed cognitive impairment including Alzheimer’s disease, vascular dementia, other/unspecified dementia, and mild cognitive impairment from 2004 to 2012. We selected 41,195 older adults without cognitive impairment through 1:1 propensity score matching using age, gender, Charlson Comorbidity Index, and index year, with follow-up throughout 2013. We eliminated subjects with mental disorders and estimated adjusted hazard ratios (AHR) of suicide deaths within one year after diagnosis using the Cox proportional hazards models. Results We identified 49 suicide deaths during the first year after cognitive impairment diagnosis. The proportion of observed suicide deaths was the highest within one year after cognitive impairment diagnosis (48.5% of total); older adults with cognitive impairment were at a higher suicide risk than those without cognitive impairment (AHR, 1.89; 95% confidence interval [CI], 1.18–3.04). Subjects with Alzheimer’s disease and other/unspecified dementia were at greater suicide risk than those without cognitive impairment (AHR, 1.94, 1.94; 95% CI, 1.12–3.38, 1.05–3.58). Suicide risk in female and young-old adults (60–74 years) with cognitive impairment was higher than in the comparison group (AHR, 2.61, 5.13; 95% CI, 1.29–5.28, 1.48–17.82). Conclusions Older patients with cognitive impairment were at increased suicide risk within one year of diagnosis. Early intervention for suicide prevention should be provided to older adults with cognitive impairment.

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