Cerebrospinal Fluid Metals and the Association with Cerebral Small Vessel Disease

J Alzheimers Dis. 2020;78(3):1229-1236. doi: 10.3233/JAD-200656.


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 APOEɛ4 carriers.

Conclusion: CSF iron levels are elevated with cerebral microbleeds in APOEɛ4 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / diagnostic imaging
  • Alzheimer Disease / genetics
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Apolipoprotein E2 / genetics
  • Apolipoprotein E4 / genetics
  • Cerebral Hemorrhage / cerebrospinal fluid
  • Cerebral Hemorrhage / diagnostic imaging
  • Cerebral Small Vessel Diseases / cerebrospinal fluid*
  • Cerebral Small Vessel Diseases / diagnostic imaging
  • Chromium / cerebrospinal fluid
  • Cognitive Dysfunction / cerebrospinal fluid*
  • Cognitive Dysfunction / diagnostic imaging
  • Cognitive Dysfunction / genetics
  • Copper / cerebrospinal fluid
  • Dementia, Vascular / cerebrospinal fluid*
  • Dementia, Vascular / diagnostic imaging
  • Diagnostic Self Evaluation
  • Female
  • Humans
  • Iron / cerebrospinal fluid
  • Magnetic Resonance Imaging
  • Male
  • Manganese / cerebrospinal fluid
  • Metals, Heavy / cerebrospinal fluid*
  • Middle Aged
  • Nickel / cerebrospinal fluid
  • Peptide Fragments / cerebrospinal fluid
  • Phosphorylation
  • Zinc / cerebrospinal fluid
  • tau Proteins / cerebrospinal fluid


  • Amyloid beta-Peptides
  • Apolipoprotein E2
  • Apolipoprotein E4
  • Metals, Heavy
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Chromium
  • Manganese
  • Copper
  • Nickel
  • Iron
  • Zinc