Tissue inhibitor of proteinase-1 and cerebral blood flow in predementia

Background
Cerebrovascular disease (CVD) can increase the risk of dementia and is frequently seen in Alzheimer’s disease. Tissue inhibitor of proteinase-1 (TIMP-1) measured in cerebrospinal fluid (CBF) is considered a promising biomarker of subcortical small vessel disease (SSVD). In addition to inhibition of matrix metalloproteases, it occurs in several biological processes, such as protection of the blood brain barrier. This study explores how TIMP-1 is associated with CBF in amyloid and non-amyloid pre-dementia cases as well as in controls.

Methods
Cases and controls, aged 40-80, were included from the Norwegian multi-site study “DDI” (n=69, age=63.2 +/- SD, m/f=26/43). Participants underwent cognitive assessment, MRI and lumbar puncture. Cases were staged as Subjective Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI). We stratified by A1-42 pathology (A+/-) using an amyloid-PET verified CSF cutoff. Cerebral blood flow (CBF) was measured with arterial spin labeling and analyzed using ExploreASL. Linear regression analysis was performed with TIMP-1 and CBF in total gray matter (GM), total white matter (WM) and several GM regions (frontal, temporal, insula, parietal, occipital, thalamus, putamen and caudate nucleus), adjusting for age and sex. CBF was log-transformed.

Results
In the A- group (n=50, age=61.6, m/f=17/33, Controls/SCD/MCI=21/22/7) there was a significant positive relationship between TIMP-1 and CBF in total GM (=-0.46, p=0.001), total WM (=-0.44, p=0.002), frontal (=-0.41, p=0.004), temporal (=-0.45, p=0.001), insula (=-0.39, p=0.006), parietal (=-0.48, p<0.001), occipital (=-0.45, p=0.001), thalamus (=-0.53, p<0.001), putamen (=-0.41, p=0.004) and caudate nucleus (=-0.48, p=0.001) GM regions. There were no significant associations in the A+ group (n=19, age=67.4, m/f=9/10, Controls/SCD/MCI=2/7/10) or in the whole sample.

Conclusion
We found that TIMP-1 correlates positively with CBF in the A- group, whereas there were no significant association in the A+ group. Putatively, this may reflect different mechanisms for vascular pathology in the two groups.