Presymptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy-Related Blood Metabolite Alterations

Author:

Chatterjee Pratishtha12,Fagan Anne M.34,Xiong Chengjie45,McKay Matthew6,Bhatnagar Atul6,Wu Yunqi6,Singh Abhay K.7,Taddei Kevin28,Martins Ian2,Gardener Samantha L.2,Molloy Mark P.69,Multhaup Gerhard10,Masters Colin L.11,Schofield Peter R.1213,Benzinger Tammie L.S.414,Morris John C.34,Bateman Randall J.34,Greenberg Steven M.15,Wermer Marieke J.H.16,van Buchem Mark A.16,Sohrabi Hamid R.1281718,Martins Ralph N.1281819,

Affiliation:

1. Department of Biomedical Sciences, Macquarie University, North Ryde, NSW, Australia

2. School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia

3. Department of Neurology, Washington University, St. Louis, MO, USA

4. Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, USA

5. Division of Biostatistics, Washington University, St. Louis, MO, USA

6. Australian Proteome Analysis Facility, Macquarie University, North Ryde, NSW, Australia

7. Macquarie Business School, Macquarie University, North Ryde, NSW, Australia

8. Australian Alzheimer’s Research Foundation, Nedlands, WA, Australia

9. Bowel Cancer and Biomarker Laboratory, Kolling Institute, The University of Sydney, St Leonards, NSW, Australia

10. Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada

11. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VA, Australia

12. Neuroscience Research Australia, Sydney, NSW, Australia.

13. School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia

14. Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA

15. Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston, Massachusetts, USA

16. Department of Radiology, Leiden University Medical Center, Leiden, Netherlands

17. Centre for Healthy Ageing, School of Psychology and Exercise Science, College of Science, Health, Engineering and Education, Murdoch University, Murdoch, WA, Australia

18. School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia

19. The KaRa Institute of Neurological Diseases, Macquarie Park, NSW, Australia

Abstract

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 < 0.05). 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.

Publisher

IOS Press

Subject

Psychiatry and Mental health,Geriatrics and Gerontology,Clinical Psychology,General Medicine,General Neuroscience

Reference33 articles.

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2. Clinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston criteria;Knudsen;Neurology,2001

3. Hereditary cerebral hemorrhage with amyloidosis-Dutch type;Maat-Schieman;Neuropathology,2005

4. DNA diagnosis for hereditary cerebral hemorrhage with amyloidosis (Dutch type);Bakker;Am J Hum Genet,1991

5. Cerebrospinal fluid amyloid beta(40) is decreased in cerebral amyloid angiopathy;Verbeek;Ann Neurol,2009

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