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Article ; Online: Cerebrospinal Fluid Neurofilament Light Predicts Risk of Dementia Onset in Cognitively Healthy Individuals and Rate of Cognitive Decline in Mild Cognitive Impairment

Kunal Dhiman / Victor L. Villemagne / Christopher Fowler / Pierrick Bourgeat / Qiao-Xin Li / Steven Collins / Ashley I. Bush / Christopher C. Rowe / Colin L. Masters / David Ames / Kaj Blennow / Henrik Zetterberg / Ralph N. Martins / Veer Gupta

Biomedicines, Vol 10, Iss 1045, p

A Prospective Longitudinal Study

2022 Volume 1045

Abstract: Background: Biomarkers that are indicative of early biochemical aberrations are needed to predict the risk of dementia onset and progression in Alzheimer’s disease (AD). We assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) chain ...

Abstract	Background: Biomarkers that are indicative of early biochemical aberrations are needed to predict the risk of dementia onset and progression in Alzheimer’s disease (AD). We assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) chain for screening preclinical AD, predicting dementia onset among cognitively healthy (CH) individuals, and the rate of cognitive decline amongst individuals with mild cognitive impairment (MCI). Methods: Neurofilament light levels were measured in CSF samples of participants (CH, n = 154 and MCI, n = 32) from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL). Cases of preclinical AD were identified using biomarker-guided classification (CH, amyloid-β [Aβ]+, phosphorylated-tau [P-tau]+ and total-tau [T-tau]±; A+T+/N±). The prediction of dementia onset (questionable dementia) among CH participants was assessed as the risk of conversion from Clinical Dementia Rating [CDR = 0] to CDR ≥ 0.5 over 6 years. Mixed linear models were used to assess the utility of baseline CSF NfL levels for predicting the rate of cognitive decline among participants with MCI over 4.5 years. Results: Neurofilament light levels were significantly higher in preclinical AD participants (CH, A+T+/N±) as compared to A-T-N- ( p < 0.001). Baseline levels of CSF NfL were higher in CH participants who converted to CDR ≥ 0.5 over 6 years ( p = 0.045) and the risk of conversion to CDR ≥ 0.5 was predicted (hazard ratio [HR] 1.60, CI 1.03–2.48, p = 0.038). CH participants with CSF NfL > cut-off were at a higher risk of developing dementia (HR 4.77, CI 1.31–17.29, p = 0.018). Participants with MCI and with higher baseline levels of CSF NfL (>median) had a higher rate of decline in cognition over 4.5 years. Conclusion: An assessment of CSF NfL levels can help to predict dementia onset among CH vulnerable individuals and cognitive decline among those with MCI.
Keywords	neurofilament light ; cerebrospinal fluid ; preclinical ; early diagnosis ; prognosis ; Biology (General) ; QH301-705.5
Subject code	150
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Amylin and beta amyloid proteins interact to form amorphous heterocomplexes with enhanced toxicity in neuronal cells

Prashant Bharadwaj / Tanya Solomon / Bikash R. Sahoo / Katarzyna Ignasiak / Scott Gaskin / Joanne Rowles / Giuseppe Verdile / Mark J. Howard / Charles S. Bond / Ayyalusamy Ramamoorthy / Ralph N. Martins / Philip Newsholme

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 14

Abstract: Abstract Human pancreatic islet amyloid polypeptide (hIAPP) and beta amyloid (Aβ) can accumulate in Type 2 diabetes (T2D) and Alzheimer’s disease (AD) brains and evidence suggests that interaction between the two amyloidogenic proteins can lead to the ... ...

Abstract	Abstract Human pancreatic islet amyloid polypeptide (hIAPP) and beta amyloid (Aβ) can accumulate in Type 2 diabetes (T2D) and Alzheimer’s disease (AD) brains and evidence suggests that interaction between the two amyloidogenic proteins can lead to the formation of heterocomplex aggregates. However, the structure and consequences of the formation of these complexes remains to be determined. The main objective of this study was to characterise the different types and morphology of Aβ-hIAPP heterocomplexes and determine if formation of such complexes exacerbate neurotoxicity. We demonstrate that hIAPP promotes Aβ oligomerization and formation of small oligomer and large aggregate heterocomplexes. Co-oligomerized Aβ42-hIAPP mixtures displayed distinct amorphous structures and a 3-fold increase in neuronal cell death as compared to Aβ and hIAPP alone. However, in contrast to hIAPP, non-amyloidogenic rat amylin (rIAPP) reduced oligomer Aβ-mediated neuronal cell death. rIAPP exhibited reductions in Aβ induced neuronal cell death that was independent of its ability to interact with Aβ and form heterocomplexes; suggesting mediation by other pathways. Our findings reveal distinct effects of IAPP peptides in modulating Aβ aggregation and toxicity and provide new insight into the potential pathogenic effects of Aβ-IAPP hetero-oligomerization and development of IAPP based therapies for AD and T2D.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Systematic review protocol for assessing central auditory functions of Alzheimer’s disease and its preclinical stages

Dona M P Jayakody / Hadeel Y Tarawneh / Holly K Menegola / Jessica M Yiannos / Peter L Friedland / Wayne J Wilson / Ralph N Martins / Hamid R Sohrabi

BMJ Open, Vol 10, Iss

2020 Volume 6

Abstract: Introduction A number of studies have reported an association between peripheral hearing impairment, central auditory processing and Alzheimer’s disease (AD) and its preclinical stages. Both peripheral hearing impairment and central auditory processing ... ...

Abstract	Introduction A number of studies have reported an association between peripheral hearing impairment, central auditory processing and Alzheimer’s disease (AD) and its preclinical stages. Both peripheral hearing impairment and central auditory processing disorders are observed many years prior to the clinical manifestation of AD symptoms, hence, providing a long window of opportunity to investigate potential interventions against neurodegenerative processes. This paper outlines the protocol for a systematic review of studies examining the central auditory processing functions in AD and its preclinical stages, investigated through behavioural (clinical assessments that require active participation) central auditory processing tests.Methods and analysis We will use the keywords and Medical Subject Heading terms to search the following electronic databases: MEDLINE, PsychINFO, PubMed, Scopus, EMBASE and CINAHL Plus. Studies including assessments of central auditory function in adults diagnosed with dementia, AD and its preclinical stages that were published before 8 May 2019 will be reviewed. This review protocol will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. Data analysis and search results will be reported in the full review. This manuscript has designed the protocols for a systematic review that will identify the behavioural clinical central auditory processing measures that are sensitive to the changes in auditory function in adults with AD and its preclinical stages. Such assessments may subsequently help to design studies to examine the potential impact of hearing and communication rehabilitation of individuals at risk of AD.Ethics and dissemination Ethical approval is not required as this manuscript only reports the protocols for conducting a systematic review as primary data will only be reviewed and not be collected. The results of this systematic review will be disseminated through publication and in scientific conferences.PROSPERO ...
Keywords	Medicine ; R
Subject code	150
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	BMJ Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Possible role of common spices as a preventive and therapeutic agent for Alzheimer′s disease

Omid Mirmosayyeb / Amirpouya Tanhaei / Hamid R Sohrabi / Ralph N Martins / Mana Tanhaei / Mohammad Amin Najafi / Ali Safaei / Rokhsareh Meamar

International Journal of Preventive Medicine, Vol 8, Iss 1, Pp 5-

2017 Volume 5

Abstract: For centuries, spices have been consumed as food additives or medicinal agents. However, there is increasing evidence indicating the plant-based foods in regular diet may lower the risk of neurodegenerative diseases including Alzheimer disease. Spices, ... ...

Abstract	For centuries, spices have been consumed as food additives or medicinal agents. However, there is increasing evidence indicating the plant-based foods in regular diet may lower the risk of neurodegenerative diseases including Alzheimer disease. Spices, as one of the most commonly used plant-based food additives may provide more than just flavors, but as agents that may prevent or even halt neurodegenerative processes associated with aging. In this article, we review the role and application of five commonly used dietary spices including saffron turmeric, pepper family, zingiber, and cinnamon. Besides suppressing inflammatory pathways, these spices may act as antioxidant and inhibit acetyl cholinesterase and amyloid β aggregation. We summarized how spice-derived nutraceuticals mediate such different effects and what their molecular targets might be. Finally, some directions for future research are briefly discussed.
Keywords	Alzheimer's disease ; dementia ; spice ; Medicine ; R
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Wolters Kluwer Medknow Publications
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Systematic Evaluation of the Use of Human Plasma and Serum for Mass-Spectrometry-Based Shotgun Proteomics

Lan, Jiayi / Antonio Núñez Galindo / Christopher Fowler / James Doecke / Loïc Dayon / Ornella Cominetti / Ralph N. Martins / Stephanie R. Rainey-Smith

Journal of proteome research. 2018 Feb. 16, v. 17, no. 4

2018

Abstract: Over the last two decades, EDTA-plasma has been used as the preferred sample matrix for human blood proteomic profiling. Serum has also been employed widely. Only a few studies have assessed the difference and relevance of the proteome profiles obtained ... ...

Abstract	Over the last two decades, EDTA-plasma has been used as the preferred sample matrix for human blood proteomic profiling. Serum has also been employed widely. Only a few studies have assessed the difference and relevance of the proteome profiles obtained from plasma samples, such as EDTA-plasma or lithium-heparin-plasma, and serum. A more complete evaluation of the use of EDTA-plasma, heparin-plasma, and serum would greatly expand the comprehensiveness of shotgun proteomics of blood samples. In this study, we evaluated the use of heparin-plasma with respect to EDTA-plasma and serum to profile blood proteomes using a scalable automated proteomic pipeline (ASAP2). The use of plasma and serum for mass-spectrometry-based shotgun proteomics was first tested with commercial pooled samples. The proteome coverage consistency and the quantitative performance were compared. Furthermore, protein measurements in EDTA-plasma and heparin-plasma samples were comparatively studied using matched sample pairs from 20 individuals from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study. We identified 442 proteins in common between EDTA-plasma and heparin-plasma samples. Overall agreement of the relative protein quantification between the sample pairs demonstrated that shotgun proteomics using workflows such as the ASAP2 is suitable in analyzing heparin-plasma and that such sample type may be considered in large-scale clinical research studies. Moreover, the partial proteome coverage overlaps (e.g., ∼70%) showed that measures from heparin-plasma could be complementary to those obtained from EDTA-plasma.
Keywords	automation ; biomarkers ; biomedical research ; blood sampling ; blood serum ; humans ; image analysis ; lifestyle ; proteins ; proteome ; proteomics
Language	English
Dates of publication	2018-0216
Size	p. 1426-1435.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.7b00788
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Efficient production of a mature and functional gamma secretase protease

Imran Khan / Sudarsan Krishnaswamy / Miheer Sabale / David Groth / Linda Wijaya / Michael Morici / Imre Berger / Christiane Schaffitzel / Paul E. Fraser / Ralph N. Martins / Giuseppe Verdile

Scientific Reports, Vol 8, Iss 1, Pp 1-

2018 Volume 15

Abstract: Abstract Baculoviral protein expression in insect cells has been previously used to generate large quantities of a protein of interest for subsequent use in biochemical and structural analyses. The MultiBac baculovirus protein expression system has ... ...

Abstract	Abstract Baculoviral protein expression in insect cells has been previously used to generate large quantities of a protein of interest for subsequent use in biochemical and structural analyses. The MultiBac baculovirus protein expression system has enabled, the use of a single baculovirus to reconstitute a protein complex of interest, resulting in a larger protein yield. Using this system, we aimed to reconstruct the gamma (γ)-secretase complex, a multiprotein enzyme complex essential for the production of amyloid-β (Aβ) protein. A MultiBac vector containing all components of the γ-secretase complex was generated and expression was observed for all components. The complex was active in processing APP and Notch derived γ-secretase substrates and proteolysis could be inhibited with γ-secretase inhibitors, confirming specificity of the recombinant γ-secretase enzyme. Finally, affinity purification was used to purify an active recombinant γ-secretase complex. In this study we demonstrated that the MultiBac protein expression system can be used to generate an active γ-secretase complex and provides a new tool to study γ-secretase enzyme and its variants.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2018-08-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Alterations in erythrocyte fatty acid composition in preclinical Alzheimer’s disease

Kathryn Goozee / Pratishtha Chatterjee / Ian James / Kaikai Shen / Hamid R. Sohrabi / Prita R. Asih / Preeti Dave / Bethany Ball / Candice ManYan / Kevin Taddei / Roger Chung / Manohar L. Garg / Ralph N. Martins

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 9

Abstract: Abstract Brain and blood fatty acids (FA) are altered in Alzheimer’s disease and cognitively impaired individuals, however, FA alterations in the preclinical phase, prior to cognitive impairment have not been investigated previously. The current study ... ...

Abstract	Abstract Brain and blood fatty acids (FA) are altered in Alzheimer’s disease and cognitively impaired individuals, however, FA alterations in the preclinical phase, prior to cognitive impairment have not been investigated previously. The current study therefore evaluated erythrocyte FA in cognitively normal elderly participants aged 65–90 years via trans-methylation followed by gas chromatography. The neocortical beta-amyloid load (NAL) measured via positron emission tomography (PET) using ligand 18F-Florbetaben, was employed to categorise participants as low NAL (standard uptake value ratio; SUVR < 1.35, N = 65) and high NAL or preclinical AD (SUVR ≥ 1.35, N = 35) wherein, linear models were employed to compare FA compositions between the two groups. Increased arachidonic acid (AA, p < 0.05) and decreased docosapentaenoic acid (DPA, p < 0.05) were observed in high NAL. To differentiate low from high NAL, the area under the curve (AUC) generated from a ‘base model’ comprising age, gender, APOEε4 and education (AUC = 0.794) was outperformed by base model + AA:DPA (AUC = 0.836). Our findings suggest that specific alterations in erythrocyte FA composition occur very early in the disease pathogenic trajectory, prior to cognitive impairment. As erythrocyte FA levels are reflective of tissue FA, these alterations may provide insight into the pathogenic mechanism(s) of the disease and may highlight potential early diagnostic markers and therapeutic targets.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2017-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Alterations in serum kynurenine pathway metabolites in individuals with high neocortical amyloid-β load

Pratishtha Chatterjee / Kathryn Goozee / Chai K. Lim / Ian James / Kaikai Shen / Kelly R. Jacobs / Hamid R. Sohrabi / Tejal Shah / Prita R. Asih / Preeti Dave / Candice ManYan / Kevin Taddei / David B. Lovejoy / Roger Chung / Gilles J. Guillemin / Ralph N. Martins

Scientific Reports, Vol 8, Iss 1, Pp 1-

A pilot study

2018 Volume 10

Abstract: Abstract The kynurenine pathway (KP) is dysregulated in neuroinflammatory diseases including Alzheimer’s disease (AD), however has not been investigated in preclinical AD characterized by high neocortical amyloid-β load (NAL), prior to cognitive ... ...

Abstract	Abstract The kynurenine pathway (KP) is dysregulated in neuroinflammatory diseases including Alzheimer’s disease (AD), however has not been investigated in preclinical AD characterized by high neocortical amyloid-β load (NAL), prior to cognitive impairment. Serum KP metabolites were measured in the cognitively normal KARVIAH cohort. Participants, aged 65–90 y, were categorised into NAL+ (n = 35) and NAL− (n = 65) using a standard uptake value ratio cut-off = 1.35. Employing linear models adjusting for age and APOEε4, higher kynurenine and anthranilic acid (AA) in NAL+ versus NAL− participants were observed in females (kynurenine, p = 0.004; AA, p = 0.001) but not males (NALxGender, p = 0.001, 0.038, respectively). To evaluate the predictive potential of kynurenine or/and AA for NAL+ in females, logistic regressions with NAL+/− as outcome were carried out. After age and APOEε4 adjustment, kynurenine and AA were individually and jointly significant predictors (p = 0.007, 0.005, 0.0004, respectively). Areas under the receiver operating characteristic curves were 0.794 using age and APOEε4 as predictors, and 0.844, 0.866 and 0.871 when kynurenine, AA and both were added. Findings from the current study exhibit increased KP activation in NAL+ females and highlight the predictive potential of KP metabolites, AA and kynurenine, for NAL+. Additionally, the current study also provides insight into he influence of gender in AD pathogenesis.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2018-05-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Plasma Amyloid-Beta Levels in a Pre-Symptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy Pedigree

Pratishtha Chatterjee / Michelle Tegg / Steve Pedrini / Anne M. Fagan / Chengjie Xiong / Abhay K. Singh / Kevin Taddei / Samantha Gardener / Colin L. Masters / Peter R. Schofield / Gerhard Multhaup / Tammie L. S. Benzinger / John C. Morris / Randall J. Bateman / Steven M. Greenberg / Mark A. van Buchem / Erik Stoops / Hugo Vanderstichele / Charlotte E. Teunissen /

Graeme J. Hankey / Marieke J. H. Wermer / Hamid R. Sohrabi / Ralph N. Martins / the Dominantly Inherited Alzheimer Network

International Journal of Molecular Sciences, Vol 22, Iss 2931, p

A Cross-Sectional and Longitudinal Investigation

2021 Volume 2931

Abstract: Plasma amyloid-beta (Aβ) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study ... ...

Abstract	Plasma amyloid-beta (Aβ) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aβ alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) mutation-carriers (MC) and non-carriers (NC) using two Aβ measurement platforms. Seventeen pre-symptomatic members of a D-CAA pedigree were assembled and followed up 3–4 years later (NC = 8;MC = 9). Plasma Aβ1-40 and Aβ1-42 were cross-sectionally and longitudinally analysed at baseline (T1) and follow-up (T2) and were found to be lower in MCs compared to NCs, cross-sectionally after adjusting for covariates, at both T1(Aβ1-40: p = 0.001; Aβ1-42: p = 0.0004) and T2 (Aβ1-40: p = 0.001; Aβ1-42: p = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aβ1-40 revealed decreased levels in MCs using data from the Simoa platform ( p = 0.041) and pairwise longitudinal analyses of plasma Aβ1-42 revealed decreased levels in MCs using data from the xMAP platform ( p = 0.041). Findings from the Simoa platform suggest that plasma Aβ may add value to a panel of biomarkers for the diagnosis of pre-symptomatic CAA, however, further validation studies in larger sample sets are required.
Keywords	amyloid-beta ; plasma amyloid-beta ; blood biomarkers ; cerebral amyloid angiopathy ; early diagnosis ; hereditary cerebral haemorrhage with amyloidosis—Dutch type ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Pathology associated with AAV mediated expression of beta amyloid or C100 in adult mouse hippocampus and cerebellum.

Eleanor S Drummond / Jill Muhling / Ralph N Martins / Linda K Wijaya / Erich M Ehlert / Alan R Harvey

PLoS ONE, Vol 8, Iss 3, p e

2013 Volume 59166

Abstract: Accumulation of beta amyloid (Aβ) in the brain is a primary feature of Alzheimer's disease (AD) but the exact molecular mechanisms by which Aβ exerts its toxic actions are not yet entirely clear. We documented pathological changes 3 and 6 months after ... ...

Abstract	Accumulation of beta amyloid (Aβ) in the brain is a primary feature of Alzheimer's disease (AD) but the exact molecular mechanisms by which Aβ exerts its toxic actions are not yet entirely clear. We documented pathological changes 3 and 6 months after localised injection of recombinant, bi-cistronic adeno-associated viral vectors (rAAV2) expressing human Aβ40-GFP, Aβ42-GFP, C100-GFP or C100(V717F)-GFP into the hippocampus and cerebellum of 8 week old male mice. Injection of all rAAV2 vectors resulted in wide-spread transduction within the hippocampus and cerebellum, as shown by expression of transgene mRNA and GFP protein. Despite the lack of accumulation of Aβ protein after injection with AAV vectors, injection of rAAV2-Aβ42-GFP and rAAV2- C100(V717F)-GFP into the hippocampus resulted in significantly increased microgliosis and altered permeability of the blood brain barrier, the latter revealed by high levels of immunoglobulin G (IgG) around the injection site and the presence of IgG positive cells. In comparison, injection of rAAV2-Aβ40-GFP and rAAV2-C100-GFP into the hippocampus resulted in substantially less neuropathology. Injection of rAAV2 vectors into the cerebellum resulted in similar types of pathological changes, but to a lesser degree. The use of viral vectors to express different types of Aβ and C100 is a powerful technique with which to examine the direct in vivo consequences of Aβ expression in different regions of the mature nervous system and will allow experimentation and analysis of pathological AD-like changes in a broader range of species other than mouse.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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