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

Article type: Research Article

Authors: Chatterjee, Pratishtha^{a; b} | Fagan, Anne M.^{c; d} | Xiong, Chengjie^{d; e} | McKay, Matthew^f | Bhatnagar, Atul^f | Wu, Yunqi^f | Singh, Abhay K.^g | Taddei, Kevin^{b; h} | Martins, Ian^b | Gardener, Samantha L.^b | Molloy, Mark P.^{f; i} | Multhaup, Gerhard^j | Masters, Colin L.^k | Schofield, Peter R.^{l; m} | Benzinger, Tammie L.S.^{d; n} | Morris, John C.^{c; d} | Bateman, Randall J.^{c; d} | Greenberg, Steven M.^o | Wermer, Marieke J.H.^p | van Buchem, Mark A.^p | Sohrabi, Hamid R.^{a; b; h; q; r} | Martins, Ralph N.^{a; b; h; r; s; *} | Dominantly Inherited Alzheimer Network

Affiliations: [a] Department of Biomedical Sciences, Macquarie University, North Ryde, NSW, Australia | [b] School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia | [c] Department of Neurology, Washington University, St. Louis, MO, USA | [d] Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, USA | [e] Division of Biostatistics, Washington University, St. Louis, MO, USA | [f] Australian Proteome Analysis Facility, Macquarie University, North Ryde, NSW, Australia | [g] Macquarie Business School, Macquarie University, North Ryde, NSW, Australia | [h] Australian Alzheimer’s Research Foundation, Nedlands, WA, Australia | [i] Bowel Cancer and Biomarker Laboratory, Kolling Institute, The University of Sydney, St Leonards, NSW, Australia | [j] Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada | [k] The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VA, Australia | [l] Neuroscience Research Australia, Sydney, NSW, Australia. | [m] School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia | [n] Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA | [o] Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston, Massachusetts, USA | [p] Department of Radiology, Leiden University Medical Center, Leiden, Netherlands | [q] Centre for Healthy Ageing, School of Psychology and Exercise Science, College of Science, Health, Engineering and Education, Murdoch University, Murdoch, WA, Australia | [r] School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia | [s] The KaRa Institute of Neurological Diseases, Macquarie Park, NSW, Australia

Correspondence: [*] Correspondence to: Professor Ralph N. Martins, PhD, School of Medical and Health Sciences, Edith Cowan University, Ralph & Patricia Sarich Neuroscience Research Institute, 8 Verdun Street, Nedlands, WA 6009, Australia. Tel.: +61 8 6304 5456; Fax: +61 8 6304 5851; E-mail: r.martins@ecu.edu.au.

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.

Keywords: Blood biomarkers, cerebral amyloid angiopathy, early diagnosis, hereditary cerebral hemorrhage with amyloidosis - dutch type, intracerebral hemorrhage, metabolomics, vascular dementia

DOI: 10.3233/JAD-201267

Journal: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 895-903, 2021