Added value of cerebrospinal fluid multimarker analysis in diagnosis and progression of dementia

Abstract

Background and purpose: Recently, some emerging cerebrospinal fluid (CSF) markers have been proposed as diagnostic tools for Alzheimer disease (AD) that can have an effect on disease progression. We analyze the accuracy of these CSF markers for diagnosis of AD in reference to brain amyloid positron emission tomography (PET). We also investigated whether they help in differentiating AD from other dementias and examined their influence in tracing the progression to dementia. Methods: Amyloid‐β (Aβ) 1–42, total tau (t‐tau), phosphorylated tau, Aβ40, Aβ38, beta‐site amyloid precursor protein cleaving enzyme 1 (BACE‐1), neurogranin (ng), phosphorylated neurofilament heavy‐chain, and α‐synuclein (α‐syn) CSF levels were analyzed in 319 subjects, among whom 57 also underwent an amyloid PET scan. We also analyzed longitudinal clinical data from 239 subjects. Results: Emerging CSF markers, especially ng/BACE‐1 ratio (area under the curve = 0.77) and their combinations with core AD CSF markers (all AUCs >0.85), showed high accuracy to discriminate amyloid PET positivity. Subjects with AD had higher CSF BACE‐1, ng, and α‐syn levels than those with non‐AD dementia. CSF t‐tau/α‐syn ratio was higher in subjects with dementia with Lewy bodies than in those with frontotemporal dementia. Most emerging/core AD ratios predicted a faster conversion from mild cognitive impairment (MCI) stage to AD and appeared to be helpful when core AD CSF markers were discordant. In addition, the rate of cognitive decline was associated with all CSF core AD markers, several emerging/core AD two‐marker ratios, and CSF ng levels. Conclusions: These results suggest that emerging biomarkers in conjunction with core AD markers improve diagnosis of AD, are associated with the conversion from MCI into AD, and predict a faster progression of dementia.

Cerebrospinal fluid markers for synaptic function and Alzheimer type changes in late life depression

“…Poorer visuospatial performance may be associated to pathology in the parietal lobe in early AD 53 . A relatively new biomarker strongly associated to cognitive performance in AD but also to differentiate AD from other underlying pathologies is the Ng/BACE ratio 54 . It has been shown that higher values of the Ng/BACE are associated with poorer memory performance in predementia AD patients 55 .…”

From Cerebrospinal Fluid Neurochemistry to Clinical Diagnosis of Alzheimer’s Disease in the Era of Anti-Amyloid Treatments. Report of Four Patients

“…Biomarkers are not stand-alone tools and should always be interpreted along with clinical, neuropsychological, and imaging data. Keeping this in mind, analysis of classical CSF biomarkers, especially when incorporated in a classification/diagnostic system such as the AT(N), may offer a significant diagnostic tool [90,91], with both added [92] and prognostic [36] value, allowing the correct identification of AD during life, especially in cases with atypical or mixed presentations [93]. This is always important for correct therapeutic decisions, and it is of paramount importance currently, due to the recent approval of aducanumab as a disease-modifying treatment.…”

Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease in the Era of Disease-Modifying Treatments

“…Keeping the above limitations in mind, biomarkers are not useful only in research, but also in clinical practice, showing both added and prognostic value [78,79]. They are not only able to confirm the presence of AD in typical cases, but they are able to identify AD in cases with atypical presentations such as primary progressive aphasia, corticobasal syndrome and posterior cortical atrophy [34,35,80,81].…”