In vivo assessment of neuroinflammation in progressive multiple sclerosis: a proof of concept study with [18F]DPA714 PET.

BACKGROUND: Over the past decades, positron emission tomography (PET) imaging has become an increasingly useful research modality in the field of multiple sclerosis (MS) research, as PET can visualise molecular processes, such as neuroinflammation, in vivo. The second generation PET radioligand [18F]DPA714 binds with high affinity to the 18-kDa translocator-protein (TSPO), which is mainly expressed on activated microglia. The aim of this proof of concept study was to evaluate this in vivo marker of neuroinflammation in primary and secondary progressive MS. METHODS: All subjects were genotyped for the rs6971 polymorphism within the TSPO gene, and low-affinity binders were excluded from participation in this study. Eight patients with progressive MS and seven age and genetic binding status matched healthy controls underwent a 60 min dynamic PET scan using [18F]DPA714, including both continuous on-line and manual arterial blood sampling to obtain metabolite-corrected arterial plasma input functions. RESULTS: The optimal model for quantification of [18F]DPA714 kinetics was a reversible two-tissue compartment model with additional blood volume parameter. For genetic high-affinity binders, a clear increase in binding potential was observed in patients with MS compared with age-matched controls. For both high and medium affinity binders, a further increase in binding potential was observed in T2 white matter lesions compared with non-lesional white matter. Volume of distribution, however, did not differentiate patients from healthy controls, as the large non-displaceable compartment of [18F]DPA714 masks its relatively small specific signal. CONCLUSION: The TSPO radioligand [18F]DPA714 can reliably identify increased focal and diffuse neuroinflammation in progressive MS when using plasma input-derived binding potential, but observed differences were predominantly visible in high-affinity binders.

Longitudinal change in ATN biomarkers in cognitively normal individuals.

BACKGROUND: Biomarkers for amyloid, tau, and neurodegeneration (ATN) have predictive value for clinical progression, but it is not clear how individuals move through these stages. We examined changes in ATN profiles over time, and investigated determinants of change in A status, in a sample of cognitively normal individuals presenting with subjective cognitive decline (SCD). METHODS: We included 92 individuals with SCD from the SCIENCe project with [18F]florbetapir PET (A) available at two time points (65 ± 8y, 42% female, MMSE 29 ± 1, follow-up 2.5 ± 0.7y). We additionally used [18F]flortaucipir PET for T and medial temporal atrophy score on MRI for N. Thirty-nine individuals had complete biomarker data at baseline and follow-up, enabling the construction of ATN profiles at two time points. All underwent extensive neuropsychological assessments (follow-up time 4.9 ± 2.8y, median number of visits n = 4). We investigated changes in biomarker status and ATN profiles over time. We assessed which factors predisposed for a change from A- to A+ using logistic regression. We additionally used linear mixed models to assess change from A- to A+, compared to the group that remained A- at follow-up, as predictor for cognitive decline. RESULTS: At baseline, 62% had normal AD biomarkers (A-T-N- n = 24), 5% had non-AD pathologic change (A-T-N+ n = 2,) and 33% fell within the Alzheimer's continuum (A+T-N- n = 9, A+T+N- n = 3, A+T+N+ n = 1). Seventeen subjects (44%) changed to another ATN profile over time. Only 6/17 followed the Alzheimer's disease sequence of A → T → N, while 11/17 followed a different order (e.g., reverted back to negative biomarker status). APOE ε4 carriership inferred an increased risk of changing from A- to A+ (OR 5.2 (95% CI 1.2-22.8)). Individuals who changed from A- to A+, showed subtly steeper decline on Stroop I (ß - 0.03 (SE 0.01)) and Stroop III (- 0.03 (0.01)), compared to individuals who remained A-. CONCLUSION: We observed considerable variability in the order of ATN biomarkers becoming abnormal. Individuals who became A+ at follow-up showed subtle decline on tests for attention and executive functioning, confirming clinical relevance of amyloid positivity.