Cortical capillary dysfunction in patients suspected of Alzheimer’s disease


      Vascular risk factors are suspected to play a role in the etiology of Alzheimer’s disease. Recently, a model that relates capillary dysfunction to the development of AD was proposed [1]. The model predicts that capillary dysfunction in form of increased capillary transit time heterogeneity (CTH) leads to inefficient oxygen extraction and eventually to tissue hypoxia. In this study we investigated regional cerebral blood flow (CBF) and CTH in cortical gray matter of AD patients and controls using dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) and surface based statistics.


      Sixteen patients with clinically suspected possible or probable AD (MMSE:24.8±2.7, age:70.4±6.3) and 19 cognitively normal (MMSE≥28) agematched (age:67.5±7.2) and healthy controls were scanned using DSC and T1-weighted (T1w) MRI. From the DSC-MRI we measured CBF, mean transit time (MTT), and CTH using a parametric model assuming a gamma distribution of the capillary transit times [2]. Capillary dysfunction was evaluated as the flownormalized CTH, the transit time coefficient of variation: TTCV=CTH/MTT. Cortical perfusion estimates were mapped onto a surface fitted to the middle layer of the subject’s individual cortex using the T1w images [3] and mapped to a standard surface in MNI space [4]. Surface based linear regression was performed to examine patient/control differences and the association between MMSE and perfusion. Age and gender were used as covariates in the analyses.


      Cortical CBF was significantly reduced bilaterally in the precuneus and parietal and temporal lobes in patients (Fig.1). Capillary dysfunction as measured by TTCV was significantly higher bilaterally in the frontal lobe, the temporal pole, and posterior cingulate gyrus in patients (Fig.1). In parts of the frontal and temporal lobes and the right cingulate gyrus we found a negative association between CBF and MMSE in patients (Fig.2). Finally, we found widespread negative correlations between TTVC and MMSE in all major lobes except the occipital lobe (Fig.2).


      Our findings are consistent with the capillary dysfunction hypothesis of AD of increased capillary transit time heterogeneity in patients. We found a negative association between CBF and MMSE. We speculate that, in these areas, CBF is increased to compensate for the rising CTH and thus the imminent capillary dysfunction.
      Figure thumbnail fx1
      Figure thumbnail fx2