Presymptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy-Related Blood Metabolite Alterations,Journal of Alzheimer’s Disease

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Presymptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy-Related Blood Metabolite Alterations
Journal of Alzheimer’s Disease ( IF 3.4 ) Pub Date : 2020-12-24 , DOI: 10.3233/jad-201267
Pratishtha Chatterjee _{1,

2} , Anne M Fagan _{3,

4} , Chengjie Xiong _{4,

5} , Matthew McKay ₆ , Atul Bhatnagar ₆ , Yunqi Wu ₆ , Abhay K Singh ₇ , Kevin Taddei _{2,

8} , Ian Martins ₂ , Samantha L Gardener ₂ , Mark P Molloy _{6,

9} , Gerhard Multhaup ₁₀ , Colin L Masters ₁₁ , Peter R Schofield _{12,

13} , Tammie L S Benzinger _{4,

14} , John C Morris _{3,

4} , Randall J Bateman _{3,

4} , Steven M Greenberg ₁₅ , Marieke J H Wermer ₁₆ , Mark A van Buchem ₁₆ , Hamid R Sohrabi _{1,

2,

8,

17,

18} , Ralph N Martins _{1,

2,

8,

18,

19} ,

Affiliation

Department of Biomedical Sciences, Macquarie University, North Ryde, NSW, Australia.
School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.
Department of Neurology, Washington University, St. Louis, MO, USA.
Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, USA.
Division of Biostatistics, Washington University, St. Louis, MO, USA.
Australian Proteome Analysis Facility, Macquarie University, North Ryde, NSW, Australia.
Macquarie Business School, Macquarie University, North Ryde, NSW, Australia.
Australian Alzheimer's Research Foundation, Nedlands, WA, Australia.
Bowel Cancer and Biomarker Laboratory, Kolling Institute, The University of Sydney, St Leonards, NSW, Australia.
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VA, Australia.
Neuroscience Research Australia, Sydney, NSW, Australia.
School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston, Massachusetts, USA.
Department of Radiology, Leiden University Medical Center, Leiden, Netherlands.
Centre for Healthy Ageing, School of Psychology and Exercise Science, College of Science, Health, Engineering and Education, Murdoch University, Murdoch, WA, Australia.
School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia.
The KaRa Institute of Neurological Diseases, Macquarie Park, NSW, Australia.

Background:Cerebral amyloid angiopathy (CAA) is one of the major causes of intracerebral hemorrhage and vascular dementia in older adults. Early diagnosis will provide clinicians with an opportunity to intervene early with suitable strategies, highlighting the importance of pre-symptomatic CAA biomarkers. Objective:Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs). Methods:Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ® p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n = 9) and non-carriers (D-CAA NCs, n = 8) from the same pedigree. Metabolites that survived correction for multiple comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults). Results:275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in theD-CAAMCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE ε4 (p < 00.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in theD-CAAMCscompared to theD-CAA NCs (p < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p < 0.01). Spermidinewas also observed to correlate with CSF Aβ40 (rs = 0.621, p = 0.024), CSF Aβ42 (rs = 0.714, p = 0.006), and brain Aβ load (rs = –0.527, p = 0.030). Conclusion:The current study provides pilot data on D-CAA linked metabolite signals, that also associated with Aβ neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia.

中文翻译：

症状前荷兰型遗传性脑淀粉样血管病相关的血液代谢物改变

背景：脑淀粉样血管病（CAA）是老年人脑出血和血管性痴呆的主要原因之一。早期诊断将为临床医生提供机会以合适的策略进行早期干预，突出了症状前 CAA 生物标志物的重要性。目的：研究荷兰型遗传性 CAA 突变携带者 (D-CAA MCs) 的症状前 CAA 相关血液代谢物改变。方法：使用质谱法（AbsoluteIDQ® p400 HR 试剂盒）测量血浆代谢物，并在出现症状前的 D-CAA MC（n = 9）和非携带者（D-CAA NC，n = 8）之间进行比较谱系。在 D-CAA MCs 和其他对照组（认知未受损的成年人）之间进一步比较了在多重比较校正后幸存下来的代谢物。结果：在对潜在混杂因素年龄、性别和 APOE ε4 进行调整后，在血浆中测量了 275 种代谢物，观察到其中 22 种在 D-CAAMCs 中显着低于 D-CAA NCs（p < 00.05）。在对多重比较进行调整后，与 D-CAA NC 相比，D-CAAMC 中只有亚精胺仍然显着较低（p < 0.00018）。D-CAA MCs 中的血浆亚精胺也显着低于认知未受损的年轻人和老年人组 (p < 0.01)。还观察到亚精胺与 CSF Aβ40（rs = 0.621，p = 0.024）、CSF Aβ42（rs = 0.714，p = 0.006）和脑 Aβ 负荷（rs = –0.527，p = 0.030）相关。结论：目前的研究提供了 D-CAA 相关代谢物信号的先导数据，

更新日期：2020-12-25

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