[Preprint] Choroid Plexus calcification correlates with cortical microglial activation in humans: a multimodal PET, CT, MRI study; 2022; Butler et al

Choroid Plexus calcification correlates with cortical microglial activation in humans: a multimodal PET, CT, MRI study
Tracy Butler, X. Hugh Wang, Gloria C. Chiang, Yi Li, Liangdong Zhou, Ke Xi, NimmiWickramasuriya, Emily Tanzi, Edward Spector, Ilker Ozsahin, Xiangling Mao, Q. RayRazlighi, Edward K. Fung, Jonathan P. Dyke, Thomas R. Maloney, Ajay Gupta, Ashish Raj, Dikoma C. Shungu, P. David Mozley, Henry Rusinek, Lidia Glodzik

Background
Choroid plexus (CP) within brain ventricles is well known to produce CSF. Additional important CP functions are now recognized including critical modulation of inflammation. Recent MRI studies have demonstrated CP enlargement in human diseases including Multiple Sclerosis and Alzheimers Disease, and in association with neuroinflammation measured using translocator protein (TSPO) PET. The basis of MRI—visible CP enlargement is unknown.

Purpose
Based on tissue studies demonstrating CP calcification as a common pathology associated with aging and disease, we hypothesized that previously—unmeasured calcium within CP contributes to MRI—measured CP volume, and may be more specifically associated with neuroinflammation.

Materials and Methods
We performed a retrospective analysis of PET—CT studies performed between 2013—2019 on a single scanner using the TSPO radiotracer 11C—PK11195. Subjects included controls (n=43) and patients diagnosed with several non—inflammatory neuropsychiatric conditions (n=46.) Cortical inflammation / microglial activation was quantified as nondisplaceable Binding Potential (BPnd.) CP and ventricle volume were measured using Freesurfer. CP calcium was measured semi—manually via tracing of low—dose CT acquired with PET and automatically using a new CT/MRI method. The contribution of CP calcium, CP overall volume, ventricle volume, subject age, sex and diagnosis to BPnd was assessed using linear regression.

Results
89 subjects (mean age 54+/—7 years; 52 men) were included. Fully—automated CP calcium quantification was accurate (ICC with semi—manual tracing = .98.) The significant predictors of cortical neuroinflammation were subject age (p=.002) and CP calcium volume (p=.041), but not ventricle or CP volume.

Conclusion
CP calcium volume can be accurately measured using low—dose CT acquired routinely with PET—CT. CP calcification — but not CP overall volume — was associated with cortical inflammation. Unmeasured CP calcification may be relevant to recent reports of CP enlargement in human inflammatory and other diseases. CP calcification may be a specific and relatively easily—acquired biomarker for neuroinflammation and CP pathology.

MedRxiv

 

This preprint has the potential to be a little jaw-dropping — in a "from the Dept. of It Was Staring Us in the Face All Along" kind of way.

We've discussed the difficulties of diagnosing neuroinflammation, by imaging or other biomarkers. Newer techniques of imaging microglial activation include MRI and PET-CT/MR with TSPO as a radiotracer.

Radiologists have learned to dismiss findings of eg increased perivascular spaces and choroid plexus calcification because they are a) quite commonly seen and b) of unknown pathological significance. CP calcification is very common in the elderly so its presence was usually put in the "accelerated ageing" basket.

Now this study is retrospectively looking at choroid plexus calcification in studies where they are proving (by non-invasive proxy) neuroinflammation and showing a correlation. This would be in the context of chronic neuroinflammation (although that may be the only type) and once established the calcification would presumably persist even if the neuroinflammation resolved, but the volume of calcification might reduce with resolution.

The authors are suggesting this might be a specific biomarker of neuroinflammation and one that is simple to obtain — a low dose non-contrast CT of the head. If this turns out to be valid many ME patients could even have their previous head CTs retrospectively evaluated.

I'll read through the paper itself and summarise some quotes.

 

OK, this is a bit confusing. Their subjects included 3 groups: "CFS" (!!), "Gulf War Syndrome" and Parkinson Disease (non-dementia), which they are characterising as "non-inflammatory neuropsychiatric" vs HCs. They are evaluating cortical microglial activation, which they seem to be differentiating from "inflammation". I may be missing something fundamental in terminology or understanding with microglial activation and neuroinflammation.

A well-cited article in Nature Reviews: Neurology: Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? (2020) said:

But maybe microglial activation can occur up to some level before neuroinflammation proper develops??

It's getting a bit late so I'll re-read tomorrow and try and follow down some of their references too. They don't give raw data but it may be in their prior papers. If anyone else has capacity to look through I'd appreciate it. Regardless I think their hypothesis is really good, so replication with 2-4x participants would be good.

TBC

 

Thank you @Hutan for backgrounding and evaluating.

Maybe it was because they were comparing the PET study, which only looked at the cortex (??): as opposed to the central grey matter. In Parkinson's they would expect neuroinflammation centrally (affecting movement), but not in the cortex in the absence of clinical evidence of dementia. It reads as if their entire participant cohort was categorised as "normal-in-terms-of-cortical-neuroinflammation", but they could closely correlate choroid plexus calcification volume with cortical microglial activity (which they considered within the range of normal?).

The key thing for us would be what do they mean by "CFS". If it's a loose diagnosis where patients might have fatigue-NOS and possibly no neuro symptoms this study will be unhelpful. But... there is potential for a similar evaluation in a well characterised group. (I wonder whether the BioBank studies that looked at pre- / post-Covid MRIs could do something with this).

I'll post some more quotes that caught my eye below.

 

I'm not sure about their comments re Fahr's disease. As you can see in the linked page there is substantial brain parenchymal calcification, so not sure how this relates to the important CP neuroinflammatory modulation functions they initially described.

We need to see their raw data. It's possible that they are showing pathological microglial activation, but which they think is in normal range, occurring in the absence of neuroinflammation (eg controlling it) when actually their framing of CFS and GWI +/- PD as non-inflammatory is incorrect to start with.

Perhaps the choroid plexus is another mechanism whereby body inflammation can be mirrored as neuroinflammation (cf VanElzakker's vagus inflammation sensing). In this case across the blood-CSF barrier rather than blood-brain barrrer.

I hope the paper's reviewers follow these points up.