Cerebrospinal Fluid Metals and the Association with Cerebral Small Vessel Disease

Article type: Research Article

Authors: Shams, Mana^{a; *} | Martola, Juha^a | Charidimou, Andreas^b | Granberg, Tobias^a | Ferreira, Daniel^c | Westman, Eric^c | Wintermark, Max^d | Iv, Michael^d | Larvie, Mykol^e | Kristoffersen Wiberg, Maria^a | Kaijser, Magnus^a | Forsgard, Niklas^f | Zetterberg, Henrik^{f; g; h; i} | Wahlund, Lars-Olof^{c; 1} | Shams, Sara^{a; d; 1}

Affiliations: [a] Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Department of Radiology, Karolinska University Hospital, Stockholm, Sweden | [b] Hemorrhagic Stroke Research Program, Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston, MA, USA | [c] Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet, Stockholm, Sweden. Division of Clinical Geriatrics, Karolinska University Hospital, Stockholm, Sweden | [d] Department of Neuroradiology, Stanford Health Care, Stanford University, Stanford, CA, USA | [e] Department of Radiology, Cleveland Clinic, Cleveland, OH, USA | [f] Clinical Chemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden | [g] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [h] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden | [i] Department of Neurodgeneration, UCL Institute of Neurology, Queen Square, London, UK | [j] UK Dementia Research Institute at UCL, London, UK

Correspondence: [*] Correspondence to: Mana Shams, MD, Department of Radiology, Karolinska University Hospital, SE-14186 Stockholm, Sweden. Tel.: +46 73 600 46 14; Fax: +46 87 11 48 40; E-mail: [email protected].

Note: [1] These two authors contributed equally to the last author position.

Abstract: Background:Brain metal homeostasis is essential for brain health, and deregulation can result in oxidative stress on the brain parenchyma. Objective:Our objective in this study was to focus on two hemorrhagic MRI manifestations of small vessel disease [cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS)] and associations with cerebrospinal fluid (CSF) iron levels. In addition, we aimed to analyze CSF biomarkers for dementia and associations with CSF metal levels. Methods:This is a cross-sectional study of 196 patients who underwent memory clinic investigation, including brain MRI. CSF was collected and analyzed for metals, amyloid-β (Aβ) 42, total tau (T-tau), and phosphorylated tau (P-tau), and CSF/serum albumin ratios. Statistical analyses were performed using generalized linear models. Results:No significant difference was found between CSF metal levels across diagnostic groups. Higher iron and copper levels were associated with higher CSF levels of Aβ42, T-tau, P-tau, and CSF/serum albumin ratios (p < 0.05). Zinc was associated with higher CSF/serum albumin ratios. There was no significant association between CMBs or cSS and CSF iron levels. An increase in CSF iron with the number of CMBs was seen in APOE ɛ4 carriers. Conclusion:CSF iron levels are elevated with cerebral microbleeds in APOE ɛ4 carriers, with no other association seen with hemorrhagic markers of small vessel disease. The association of elevated CSF iron and copper with tau could represent findings of increased neurodegeneration in these patients.

Keywords: Alzheimer’s disease, cerebrospinal fluid, cognitive aging, dementia, magnetic resonance imaging

DOI: 10.3233/JAD-200656

Journal: Journal of Alzheimer's Disease, vol. 78, no. 3, pp. 1229-1236, 2020