APP‐derived peptides reflect neurodegeneration in frontotemporal dementia

Abstract

ObjectiveWe aimed to investigate the relationship between cerebrospinal fluid levels (CSF) of amyloid precursor protein (APP)‐derived peptides related to the amyloidogenic pathway, cortical thickness, neuropsychological performance, and cortical gene expression profiles in frontotemporal lobar degeneration (FTLD)‐related syndromes, Alzheimer’s disease (AD), and healthy controls.MethodsWe included 214 participants with CSF available recruited at two centers: 93 with FTLD‐related syndromes, 57 patients with AD, and 64 healthy controls. CSF levels of amyloid β (Aβ)1‐42, Aβ1‐40, Aβ1‐38, and soluble β fragment of APP (sAPPβ) were centrally analyzed. We compared CSF levels of APP‐derived peptides between groups and, we studied the correlation between CSF biomarkers, cortical thickness, and domain‐specific cognitive composites in each group. Then, we explored the relationship between cortical thickness, CSF levels of APP‐derived peptides, and regional gene expression profile using a brain‐wide regional gene expression data in combination with gene set enrichment analysis.ResultsThe CSF levels of Aβ1‐40, Aβ1‐38, and sAPPβ were lower in the FTLD‐related syndromes group than in the AD and healthy controls group. CSF levels of all APP‐derived peptides showed a positive correlation with cortical thickness and the executive cognitive composite in the FTLD‐related syndromes group but not in the healthy control or AD groups. In the cortical regions where we observed a significant association between cortical thickness and CSF levels of APP‐derived peptides, we found a reduced expression of genes related to synaptic function.InterpretationAPP‐derived peptides in CSF may reflect FTLD‐related neurodegeneration. This observation has important implications as Aβ1‐42 levels are considered an indirect biomarker of cerebral amyloidosis.

Diagnostic Utility of Measuring Cerebral Atrophy in the Behavioral Variant of Frontotemporal Dementia and Association With Clinical Deterioration

“… 38 Our results support the view that many of these bvFTD mimics could be identified at the first clinical encounter with reproducible measures of cerebral atrophy. Additional studies are needed to investigate the role of other novel promising neuroimaging or fluid biomarkers such as cortical mean diffusivity 39 or neurofilament light chain levels in plasma 40 to increase the diagnostic accuracy of VAS and to differentiate bvFTD cases without underlying FTLD.…”

The Aβ1–42/Aβ1–40 ratio in CSF is more strongly associated to tau markers and clinical progression than Aβ1–42 alone

“…We included all participants in the Sant Pau Initiative on Neurodegeneration (SPIN) cohort [ 23 ] that underwent lumbar puncture for CSF biomarkers between November 2013 and August 2021. The diagnostic groups included patients with mild cognitive impairment (MCI) or dementia and with either pathophysiological evidence of Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD)-related syndromes [ 24 , 25 ], or probable dementia with Lewy bodies (DLB). Diagnoses were established following internationally accepted diagnostic criteria [ 6 , 7 , 9 , 26 – 28 ].…”

Sex differences in the behavioral variant of frontotemporal dementia: A new window to executive and behavioral reserve

“…Detailed cognitive functioning was assessed using two previously published neuropsychological protocols 2,28 . We selected cognitive measures from each protocol measuring parallel neuropsychological constructs, and we defined four main neuropsychological domains (memory, executive functioning, language, and visuospatial functioning) as in previous multicenter studies 32,33 . Details on the neuropsychological protocols can be found in Supplementary Methods and Table S2.…”