Annals of neurologyJournal Article
undefined Jul 2025
The goal was to examine the effect of sociodemographic variables, Alzheimer's disease (AD) clinical stages and pathology on brain metabolism in Down syndrome (DS).
We included 71 euploid healthy controls (HC) and 105 adults with DS (67 asymptomatic, 12 prodromal, and 26 with dementia) from the Down-Alzheimer Barcelona Neuroimaging Initiative. Participants underwent [18F]fluorodeoxyglucose positron emission tomography, 3 Tmagnetic resonance imaging, and lumbar puncture to measure cerebrospinal fluid (CSF) biomarkers (ratio beween amyloid β peptide 42 and 40, phosphorylated tau 181, and neurofilament light chain [NfL]). Voxel-wise analyses in SPM12 examined the effects of age, sex, intellectual disability, Alzheimer's clinical stage, and CSF biomarkers on brain metabolism.
In HC, brain metabolism decreased with age primarily in the frontal lobe. By contrast, a more distributed pattern of metabolic loss was observed in DS with age, predominating in temporoparietal regions. Compared to asymptomatic DS participants, those at the prodromal stage exhibited medial parietal hypometabolism, which later extended to other temporoparietal and frontal regions at the dementia stage. In asymptomatic individuals, we observed a widespread hypometabolism compared to HC, mainly in medial frontal and parietal regions. All CSF biomarkers were closely associated with hypometabolism in regions affected by the disease, with the strongest association observed for NfL in medial parietal structures.
The brain metabolic decline in DS with age reflects Alzheimer's pathological processes and involves temporoparietal regions in a similar pattern to that found in other forms of AD. Hypometabolism is more tightly related to CSF NfL levels than to core AD biomarkers. ANN NEUROL 2025;98:163-173.
Potential Conflicts of Interest. M.R.A. reported serving as a consultant for Veranex, and being a partner and director of production at Masima – Soluções em Imagens Médicas LTDA. A.L. reported serving as a consultant for Almirall, Fujirebio-Europe, Roche, Biogen, Grifols, Novartis, Otsuka, Eisai, Lilly, Nutricia, and Zambon, and holding a patent on markers of synaptopathy in neurodegenerative disease (licensed to ADx, EPI8382175.0). D.A. reported serving as a consultant for Fujirebio-Europe, Roche Diagnostics, Grifols S.A., and Lilly, receiving honoraria for lectures or educational events from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U., Neuraxpharm, Lilly, and Esteve Pharmaceuticals S.A., and holding a patent on synaptopathy in neurodegenerative disease (WO2019175379 A1). J.F. reported serving as a consultant for Lundbeck, Ionis, and AC Immune; receiving honoraria from Roche, Esteve, Biogen, Laboratorios Carnot, Adamed, LMI, Eisai, and Lilly; serving on advisory boards for AC Immune, Alzheon, Zambon, Lilly, Roche, Eisai, and Perha; holding a patent for markers of synaptopathy (WO2019175379 A1); holding unpaid roles with the Spanish Neurological Society, T21 Research Society, Lumind Foundation, Jérôme Lejeune Foundation, Alzheimer’s Association, Health Research Board (HRB), Dementia Trials Ireland, the European Commission, the National Institutes of Health, and the Instituto de Salud Carlos III; and receiving services from Life Molecular Imaging. M.C.I. reported receiving honoraria for educational events from Esteve, Lilly, Neuraxpharm, Roche, and Adium, and serving on an advisory board for Roche. J.E.A.I. reported receiving honoraria for educational events from Roche, and receiving travel support from Nutricia. V.C. reported receiving institutional support for educational events from Lilly, General Electric, and Life Molecular Imaging (LMI). I.B. reported receiving honoraria for educational events from Adium. J.A. reported receiving honoraria for educational events from Lilly, Roche, and Esteve.
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