Cerebrospinal Fluid Biomarkers Predict Clinical Evolution in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment

Abstract

Background: Determination of Alzheimer's disease (AD) by cerebrospinal fluid (CSF) biomarkers - 42-amino-acid amyloid-β (Aβ₄₂), total tau and phosphorylated tau (p-tau) - has demonstrated high validity for detecting AD neuropathological changes. However, their prognostic utility to predict the onset of dementia in predementia subjects is still questioned. We aimed to study the prospective clinical evolution of a group of subjects with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) and to determine the prognostic capacity of AD CSF biomarkers. Methods: 149 subjects with MCI or SCD, not meeting dementia criteria, underwent a prospective clinical, neuropsychological and CSF biomarker study. Patients were initially classified as SCD or MCI following internationally accepted criteria. CSF sampling was obtained and analysed following consensus protocols. Neuropsychological and clinical evaluations were conducted at the follow-up. Statistical analysis considering the final clinical diagnosis, regression analysis to define risk factors and survival curves for progression were made. Results: 72.4% of subjects (83% MCI and 27% SCD) with a pathological CSF ratio (Aβ₄₂/p-tau) met criteria for dementia during the 5-year follow-up versus 18.7% of subjects from the group with a normal ratio. The pathological CSF ratio was a powerful marker of risk for AD dementia (OR 27.1; 95% CI 10.3-71.2). Kaplan-Meier survival curves showed that only 15% of subjects with a pathological CSF ratio remained free of AD dementia at 5 years of follow-up. All subjects who reverted to normal cognition presented a normal CSF profile at baseline. Conclusion: An abnormal AD CSF biomarker profile in predementia subjects is a powerful predictor of cognitive and/or functional decline in the medium term.

Longitudinal evaluation of criteria for subjective cognitive decline and preclinical Alzheimer's disease in a memory clinic sample

“…The present study findings are more in line with a second study of similar sample size reporting that the preclinical AD stages predicted an incremental cognitive decline for each stage over a mean (SD) of 2 (1) years [40]. In a third recent study, 27% ( n  = 3) of patients with SCD and a pathologic CSF ratio (Aβ42/p-tau) developed ADD within 5 years [41]. The most comparable diagnostic category in our study would be the NIA-AA stage 2 that had a similar proportion of dementia converters (24%) although only 14% to ADD.…”

“…This may be associated with the relatively young age of the patient group [42]. Consistent with previous research [40,41] CSF Ab42 was the only significant single predictor of cognitive decline. This is also in line with the model proposed by Jack et al [43], describing a temporal evolution of AD with changes in CSF Ab42 occurring first.…”

Quantitative Proteomic Profiling of Cerebrospinal Fluid to Identify Candidate Biomarkers for Alzheimer's Disease

“…First, we investigated the list of known biomarkers to ascertain whether they are differentially regulated in the same direction as other studies. Microtubule associated protein tau (MAPT) showed a 2.4-fold upregulation in AD CSF as previously reported [28]. Glial fibrillary acidic protein (GFAP) is also known as a marker of astrocytosis in neurodegeneration associated with neurological disorders.…”

Apolipoprotein E e4 Allele Is Associated with Subjective Cognitive Decline: A Meta-Analysis

“…We selected 28 studies described in 26 articles [11-13, 20, 24-45]. The study of Norberg et al [20] was divided into 3 parts (northern ­Europe, middle Europe, and southern Europe), so there are 2 more studies other than the number of articles.…”