Introduction

White matter hyperintensities (WMH) in Fluid Attenuated Inversion Recovery (FLAIR) images have been widely observed in patients with cerebral small vessel disease (CSVD), Alzheimer’s disease (AD), or a mixed CSVD and AD pathology. WMH is strongly associated with progression to dementia. Thus far, the pathogenesis of WMH has been poorly understood. Post-mortem histological studies showing activated microglia, and the presence of inflammatory markers in the blood (CRP) and CSF (matrix metalloproteases and albumin).59,60 More recently, increased and persistent systemic inflammation (measured by CRP) in midlife was found to promote late-life white matter structural injury.36,37 However, there is no in vivo data from patients to provide direct evidence. In addition, because of the high prevalence of mixed CSVD and AD pathology in elderly with WMH, it is unclear whether amyloid deposition, a hallmark early pathological features of AD, may also contribute to WMH. In this study, we sought to evaluate whether WMH burden is associated with neuro-inflammation and amyloid deposition using PET and MR imaging. Moreover, we examined whether neuro-inflammation elevation is region specific.

Material & Methods

¹¹C-PK11195 radiotracer binds to activated microglia. Thus it can be used as a molecular imaging biomarkers to measure in vivo inflammation using PET. 19 elderly subjects (12 females, age: 75 [68, 82] (Median [interquartile range IQR])) with various degrees of WMH were recruited and underwent serial PET and MR scans. ¹¹C-PK11195 PET images were acquired to estimate neuro-inflammation. In addition, 11C-PiB PET images, to measure amyloid deposition, were acquired 9-24 months (19 [14, 22] (Median [IQR]) prior to the PET ¹¹C-PK11195 scans from the same patients. WMH lesions were manually outlined using MR FLAIR images and WMH volume is then computed. Moreover, MR T1w MPRage images were used to segment brain tissue into gray matter, white matter and CSF. To account for inter-subject variations in brain tissue volumes, relative WMH (rVWMH) is calculated as a ratio between absolute WMH volume and a summation of gray matter and white matter volumes. All PET and MR images were registered to a FreeSurfer atlas. Median standardized uptake value (SUV) of the cerebellum gray matter was utilized to compute SUV Ratio (SUVR) maps.

Results

5 out of 18 patients had a clinical dementia rating (CDR) score greater than 0.5 (CDR=0.5, n=3, CDR=1, n=2). The median and IQR WMH lesion volumes were 8.4 ml [3.6ml 24.1ml]. We found that white matter 11C-PK11195 uptake was significantly higher in subjects with high WMH burden compared to subjects with low WMH burden N=8), while GM uptake did not differ (Fig 1). Univariate linear regression demonstrates that WMH burden is significantly associated with 11C-PK11195 uptake in white matter (Fig 2A, R=0.55, P<0.01) as a weaker association with age (Fig 2B, R=0.51, P<0.05). After adjusting for age, PK uptake shows a near-significant association with WMH burden (Fig 2D, R=0.6, P=0.08). Interestingly, there was no correlation between WMH volumes and amyloid deposition as measured by 11C-PiB PET (Fig 2C, R=-0.17, P=0.50), or with CDR score (data not shown, R = 0.3061 and P = 0.11).

Discussion

Translocator protein (TSPO) is expressed on microglia and expression is strongly upregulated upon microglial activation. Autoradiography combined with immunohistochemical staining demonstrate that PK11195 binds to activated microglia in human postmortem brains and in animal models of neurological diseases, thus providing an imaging tool to measure in vivo inflammation.62,63 PET 11C-PK11195 tracer binds to activated microglia and provides a means for imaging neuroinflammation in living humans.60 We have demonstrated that increasing white matter 11C-PK11195 uptake correlate with an increase in WMH volume suggesting the presence of increased inflammation as an index of disease severity. In contrast, PiB uptake, a biomarker of amyloid deposition, is not associated with WMH.

Conclusions

Our results demonstrated that neuro-inflammation is selectively elevated in the white matter and significantly correlates with WMH burden. On the other hand, amyloid deposition is not associated with WMH.

Acknowledgements

No acknowledgement found.

References

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