Presymptomatic Dutch-type hereditary cerebral amyloid angiopathy-related blood metabolite alterations

Chatterjee, P.; Fagan, A.M.; Xiong, C.J.; McKay, M.; Bhatnagar, A.; Wu, Y.Q.; Singh, A.K.; Taddei, K.; Martins, I.; Gardener, S.L.; Molloy, M.P.; Multhaup, G.; Masters, C.L.; Schofield, P.R.; Benzinger, T.L.S.; Morris, J.C.; Bateman, R.J.; Greenberg, S.M.; Wermer, M.J.H.; Buchem, M.A. van; Sohrabi, H.R.; Martins, R.N.; Dominantly Inherited Alzheimer Net

doi:doi:10.3233/JAD-201267

Objective: Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs).Methods: Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ (R) p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n= 9) and non-carriers (D-CAA NCs, n= 8) from the same pedigree. Metabolites that survived correction for multiple comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults).Results: 275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in the D-CAA MCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE epsilon 4 (p < 00.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in the D-CAA MCs compared to the D-CAA NCs (p < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively...Show moreObjective: Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs).Methods: Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ (R) p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n= 9) and non-carriers (D-CAA NCs, n= 8) from the same pedigree. Metabolites that survived correction for multiple comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults).Results: 275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in the D-CAA MCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE epsilon 4 (p < 00.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in the D-CAA MCs compared to the D-CAA NCs (p < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p < 0.01). Spermidine was also observed to correlate with CSF A beta(40) (r(s) = 0.621, p = 0.024), CSF A beta(42) (r(s) = 0.714, p = 0.006), and brain A beta load (r(s) = -0.527, p = 0.030).Conclusion: The current study provides pilot data on D-CAA linked metabolite signals, that also associated with A beta neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia.Show less

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Presymptomatic Dutch-type hereditary cerebral amyloid angiopathy-related blood metabolite alterations