DOI: 10.1002/alz.079680 ISSN: 1552-5260

Analysis of blood and cerebrospinal fluid flows in preclinical AD. Preliminary results from ALFA+ cohort

Carles Falcon, Celia Mansilla‐Usero, Carla Morante‐Alberti, Kaj Blennow, Henrik Zetterberg, Gwendlyn Kollmorgen, Margherita Carboni, Oriol Grau‐Rivera, Carolina Minguillon, Marc Suarez‐Calvet, Juan Domingo Gispert,
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Intracranial cerebrospinal fluid (CSF) motion is driven by the wave pressure associated with arterial blood flow into the skull (Figure 1). Since one of the roles of CSF is the clearance of neural waste, it was investigated the relationship between blood and CSF flow parameters (as measured by magnetic resonance imaging [MRI]) and CSF Ab42/40 and ptau‐181 levels in the preclinical stages of Alzheimer’s disease (AD).


Three hundred sixty‐five subjects from the ALFA+ cohort underwent two MRI phase‐encoded velocity sequences (30 frames per cardiac cycle) to measure (1) blood flow in carotids below carotid bifurcation and (2) CSF flow through foramen magnum. The scanner’s Q‐flow tool was used to quantify stroke volume (volume per cardiac cycle), percent of vessel’s area increase and flow velocity increase, as a proxy for vessel elasticity and flow pulsatility, respectively. Associations between flow parameters and age, CSF Ab42/40 and ptau‐181 concentrations were sought, correcting for sex, age and time between lumbar puncture and MRI (P<0.05).


One hundred thirty‐two subjects were excluded because the scanning session was not completed, showed missing or outlier values or did not pass quality control (artifacts or unbalanced outwards‐inwards CSF flow measures), resulting in a final sample size of 233 participants (mean age [SD]: 60.8±4.5 years; male: n = 73 [31.3%]). Figure 2 shows the plots with the most significant relationships between flow parameters, CSF biomarkers, CSF volume and age. It was observed that a higher stroke volume in CSF flow was associated with lower Ab42/40 and higher ptau‐181 concentrations in CSF.


These results indicate that, despite the role of CSF in waste clearance, the accumulation of amyloid and tau in the brain might be neither caused nor enhanced by a global deficit in CSF circulation. We hypothesize that a higher volume of CSF associated with age and high ptau‐181 levels and/or the loss of parenchyma elasticity might reduce the global intracranial compressibility, resulting in an enhanced response to pressure increase due to blood flow into the skull, which could explain the observed increase in CSF flow associated with the early stages of AD.

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