Validation of the Alzheimer’s dementia conversion-related pattern (ADCRP) as a biomarker of neurodegeneration within the novel NIA-AA research framework of Alzheimer’s disease

Introduction: According to the novel NIA-AA research framework [1], Alzheimer’s disease (AD) is defined by underlying pathological processes that can be documented by in vivo biomarkers of β amyloid deposition (“A”), pathological tau (“T”), and neurodegeneration [“(N)”]. In the present study, we examined the validity of a previously established pattern expression score (PES) of the Alzheimer’s dementia conversion-related pattern (ADCRP) on FDG PET as an AD-specific biomarker of neurodegeneration and possible predictor of conversion from mild cognitive impairment (MCI) to AD dementia.

Methods: Datasets of 281 MCI subjects from the ADNI database with available FDG PET, AV45 PET, CSF phosphorylated tau (P-tau) and total tau (T-tau) data were included. ADCRP PES was obtained by principal component analysis (PCA) [2] as recently published [3]. β amyloid load was assessed by calculation of the standardized uptake value ratio in AD-typical regions using cerebellum as reference. Biomarker values were classified as positive if AV45 SUVR > 1.3 (A) and P-tau concentration > 26.6 pg/mL (T). Based on AV45 SUVR and CSF P-tau, patients were categorized to the following groups: A-T- (normal AD biomarkers), A+T- (Alzheimer’s pathologic change), A+T+ (AD) and A-T+ (non-AD pathologic change). We compared PES between aforementioned groups, and assessed its prognostic value in prediction of conversion from MCI to dementia within the A+T+ group (Cox proportional hazards regression). Finally, all biomarkers were investigated for stratification of subjects according to their risk of conversion.

Results: 24% of all subjects converted to dementia (median follow-up based on inversed Kaplan-Meier method: 48 months [95% CI: 47-48 months]). 139 subjects were categorized as A+T+ (41% of which converted to AD dementia). The ADCRP PES was significantly increased in the A+T+ group compared to all other groups (all p < 0.005) but was similar among the latter. Within the A+T+ group, PES was a significant predictor of conversion to dementia, and it was a better predictor than T-tau, an alternative biomarker of the “(N)” group (HR of 1.12 vs. 1.00, p < 0.001). Stratification of A+T+ subjects by PES into three equally-sized groups yielded well-separated groups of high-, medium- and low-risk of conversion with median conversion times of 26, 47 and 120 months, respectively. AV45 uptake, P-tau concentration or T-tau concentrations did not allow for a reliable stratification of A+T+ subjects into risk groups. Moreover, PES was also found to be a significant predictor in A+T- group (p < 0.05) but not in A-T+ or A-T- groups.

Conclusions: Our results suggest that ADCRP PES is a rather AD-specific biomarker of neurodegeneration. It shows great promise for stratifying the risk and estimating the time to conversion to dementia in A+T+ MCI subjects, which is of great interest for clinical practice and future trials. References: 1. Jack C.R. Jr et al., NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018 Apr; 14(4):535-562. doi: 10.1016/j.jalz.2018.02.018. 2. Blazhenets G. et al., Principal component analysis of brain metabolism predicts development of Alzheimer's dementia. J Nucl Med. 2018 Nov 2. pii: jnumed.118.219097. doi: 10.2967/jnumed.118.219097. 3. Eidelberg D. Metabolic brain networks in neurodegenerative disorders: a functional imaging approach. Trends Neurosci. 2009; 32:548-557.