Contribution of CSF biomarkers to early‐onset Alzheimer's disease and frontotemporal dementia neuroimaging signatures

Abstract

Prior studies have described distinct patterns of brain gray matter and white matter alterations in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), as well as differences in their cerebrospinal fluid (CSF) biomarkers profiles. We aim to investigate the relationship between early-onset AD (EOAD) and FTLD structural alterations and CSF biomarker levels. We included 138 subjects (64 EOAD, 26 FTLD, and 48 controls), all of them with a 3T MRI brain scan and CSF biomarkers available (the 42 amino acid-long form of the amyloid-beta protein [Aβ42], total-tau protein [Ttau], neurofilament light chain [NfL], neurogranin [Ng], and 14-3-3 levels). We used FreeSurfer and FSL to obtain cortical thickness (CTh) and fraction anisotropy (FA) maps. We studied group differences in CTh and FA and described the "AD signature" and "FTLD signature." We tested multiple regression models to find which CSFbiomarkers better explained each disease neuroimaging signature. CTh and FA maps Neus Falgàs, Mariona Ruiz-Peris, Albert Lladó, and Raquel Sánchez-Valle authors contributed equally to this work.

Longitudinal brain atrophy and CSF biomarkers in early-onset Alzheimer’s disease

“…At baseline, we described lower CTh in EOAD in the bilateral parietal, precuneus, and posterior cingulate as well as in the lateral temporal lobes and right occipital cortices. Previous cross-sectional MRI studies have also found widespread brain atrophy in EOAD, particularly in parietotemporal areas when compared to LOAD ( Aziz et al, 2017 , Falgàs et al, 2020 , Harper et al, 2017 , Möller et al, 2013 , Ossenkoppele et al, 2015a ). We found that the thickness of the entorhinal and parahippocampal cortices was preserved at the time of diagnosis, in consonance with studies describing greater pathological burden ( Murray et al, 2011 , Whitwell et al, 2012 ) and greater Tau deposit outside the MTL at younger ages ( La Joie et al, 2020 , Schöll et al, 2017 ).…”

“…Higher CSF Aβ42 levels, within pathological range, were associated with faster cortical loss in precuneus and superior parietal cortices in the two EOAD cohorts, but not in LOAD subjects. CSF Aβ42 levels have been related to EOAD GM loss in cross-sectional studies ( Falgàs et al, 2020 , Ossenkoppele et al, 2015b ). Although AD biomarkers of neurodegeneration become abnormal after amyloid biomarkers ( Jack et al, 2018 ), rates of atrophy might accelerate before the conventional thresholds of CSF Aβ42 positivity ( Insel et al, 2016 ).…”

“…Similar to LOAD patients, the presence of low levels of CSF amyloid-β1-42 (Aβ42) with high levels of phosphorylated Tau (p-tau) and total Tau (t-tau) define the diagnosis in EOAD ( Jack et al, 2018 , McKhann et al, 2011 ). Some studies have suggested that baseline CSF Tau and neurofilament light chain (NfL) levels could predict longitudinal atrophy in AD ( Fjell et al, 2010 , Tarawneh et al, 2015 , Zetterberg et al, 2016 ), and baseline Aβ42 levels have been previously correlated with the pattern of atrophy in EOAD ( Falgàs et al, 2020 , Ossenkoppele et al, 2015b ).…”

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“…We observed a positive correlation between CSF brain volume and PAD score for each group. Nevertheless, EOAD patients had higher CSF brain volume than controls, which was in agreement with the previous studies on EOAD and LOAD patients (Anoop et al, 2010;Teng et al, 2014;Chiaravalloti et al, 2016;Falgàs et al, 2020b). The correlations were also consistent with the attention maps showing the involvement of the junction between the GM and the CSF in the brain age prediction.…”

Neurogranin and Neuronal Pentraxin Receptor as Synaptic Dysfunction Biomarkers in Alzheimer’s Disease

“…Likewise, we did not observe a significant correlation between Ng levels and MMSE in the patients with dementia. The findings of other researchers concerning the correlation between Ng and MMSE are also inconclusive [ 45 , 46 , 75 ]. In the AD group, we observed a significant association between increased Ng and pTau181, which agrees with other investigations [ 34 , 45 , 46 , 58 ].…”