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CSF Aβ42, P‐tau and noradrenaline metabolite MHPG levels are synergistically related to cortical thickness in a memory clinic population
Author(s) -
van Hooren Roy W.E.,
Verhey Frans R.J.,
Ramakers Inez H.G.B.,
Jansen Willemijn J.,
Jacobs Heidi I.L.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.037481
Subject(s) - locus coeruleus , cerebrospinal fluid , medicine , population , metabolite , psychology , cognition , pathology , endocrinology , neuroscience , central nervous system , environmental health
Abstract Background The earliest signs of tau pathology have been traced back to the locus coeruleus (LC). The LC is the primary site for the synthesis of noradrenaline in the brain and there is evidence for LC volume loss as early as preclinical Braak stage 1 of Alzheimer's disease (AD). Increased levels of a noradrenaline metabolite called 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) have been found in advanced AD, while there is also a correlation between MHPG levels and cognitive performance. Additionally, MHPG may be an upstream driver of amyloid and tau pathology in AD, while both of these hallmark pathologies are linked to cortical thickness. Therefore, this study investigates the association between the noradrenergic system and AD pathology in relation to cortical thickness as a measure of structural brain morphology. Method The study sample included a total of 77 patients from the memory clinic with a mean age of 63 years, of whom 49 (64%) were male. Of this sample, 36 patients had subjective memory complaints (cognitively unimpaired) and 41 patients were cognitively impaired (mild cognitive impairment or AD). All patients had complete cerebrospinal fluid (CSF) measures of MHPG, Aß42 and p‐tau. Vertex‐based cortical thickness analyses were performed using FreeSurfer V6.0 while correcting for age, sex, education and MMSE score. Critical p‐values were adjusted for multiple comparisons using cluster‐based correction. Result Results showed interaction effects between MHPG levels and AD pathology to predict cortical thickness. As MHPG levels increased, both lower levels of CSF Aß42 and higher levels of CSF p‐tau were incrementally associated with lower cortical thickness. Moreover, higher AD signature p‐tau/Aß42 ratio was similarly associated with lower cortical thickness as MHPG increased. Results remained significant after the addition of apolipoprotein E4 information. Conclusion Our results suggest that synergistic relationships exist between MHPG, levels of AD pathology and cortical thickness. These findings provide support for an influential role of the noradrenergic system in AD, in tandem with established AD pathologies. These results suggest that in addition to clinical trials focusing on amyloid and tau pathologies, noradrenergic targets for pharmaceutical interventions may also be a promising focus.

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