Visser PJ, Verhey F, Knol DL, Scheltens P, Wahlund LO, Freund-Levi Y et al. Prevalence and prognostic value of CSF markers of Alzheimer’s disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurol 8: 619-627
Alzheimer's disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group.
Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Abeta(42):tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia.
The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26.8, 95% CI 1.6-456.4).
AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up.
European Commission; Ana Aslan International Foundation.
"CSF levels of A␤ and phospho-tau are abnormal in AD, with decreased levels of A␤, and increased phospho-tau compared to cognitively normal controls   . In MCI, lower baseline A␤ and higher phospho-tau is associated with more rapid cognitive decline, greater cortical thinning, and increased likelihood of transition to dementia of the Alzheimer's type (DAT)     . Critically for the present study, CSF levels of A␤ and phospho-tau from lumbar puncture are significantly correlated with cortical brain biopsy histology, suggesting they are adequate surrogates for ex vivo histopathological measurements  . "
[Show abstract][Hide abstract] ABSTRACT: Alzheimer’s disease (AD) is characterized by two primary pathologies: tau-related neurofibrillary tangles and the extracellular accumulation of amyloid-β (Aβ). The development of these pathologies is topologically distinct early in the disease, with Aβ beginning to accumulate as a diffuse, neocortical pathology, while tau-related pathology begins to form in mesial temporal regions. This study investigated the hypothesis that, by virtue of this distinction, there exist preferential associations between the primary pathologies and aspects of the cognitive phenotype. We investigated the relationship between cerebrospinal fluid (CSF) biomarkers for tau and Aβ pathologies with neurocognitive measures in 191 patients with mild cognitive impairment (MCI). Participants completed cognitive tests of new learning, information processing speed, and working memory. Separate regression models were computed and then followed up with mediation analyses to examine the predictive status of CSF biomarkers. The effect of Aβ on learning was mediated by phospho-tau (p = 0.008). In contrast, Aβ had a direct effect on information processing speed that was not mediated by phospho-tau (p = 0.59). No predictors were significant for working memory. This study provided evidence for a differential relationship of Aβ and phospho-tau pathologies on the neurocognitive phenotype of MCI. This supports the proposition that these primary AD pathologies maximally affect different aspects of cognition, and has potential implications for cognitive assessments and the use of biomarkers in disease-modifying therapeutic trials.
"Examples include the Innotest Amyloid-Tau Index (IATI) defined by the ratio A␤ 1-42 /(240+1.18 × tau)  , the AD-CSF-Index   , and the ratios T-tau/A␤ 1-42 or P-tau 181p /A␤ 1-42 . These proposed diagnostic algorithms, however, were constructed initially to discriminate AD patients from cognitively normal controls but not to distinguish between MCI patients who have developed AD over time and those who remained stable. "
[Show abstract][Hide abstract] ABSTRACT: Abstract Background: Cerebrospinal fluid (CSF) biomarkers can distinguish Alzheimer’s disease (AD) patients from normal controls; however, their interpretation and potential for use in patients with mild cognitive impairment (MCI) remains unclear. Objective: To examine whether biomarker levels allow for risk stratification among MCI patients who are at increased risk to develop AD, thus allowing for improved targeting of early interventions for those whose risk are higher. Methods: We analyzed data from the Alzheimer’s Disease Neuroimaging Initiative on MCI patients (n = 195) to estimate their risk of developing AD for up to 6 years on the basis of baseline CSF biomarkers. We used time-dependent receiver operating characteristic analysis to identify the best combination of biomarkers to discriminate those who converted to AD from those who remained stable. We used these data to construct a multi-biomarker score and estimated the risk of progression to AD for each quintile of the multi-biomarker score. Results: We found that Aβ 1-42 and P-tau181p were the best combination among CSF biomarkers to predict the overall risk of developing AD among MCI patients (area under the curve = 0.77). The hazard ratio of developing AD among MCI patients with high-risk (3rd–5th quintiles) biomarker levels was about 4 times greater than MCI patients with low-risk (1st quintile) levels (95% confidence interval, 1.93–7.26). Conclusion: Our study identifies MCI patients at increased risk of developing AD by applying a multi-biomarker score using CSF biomarker results. Our findings may be of value to MCI patients and their clinicians for planning purposes and early intervention as well as for future clinical trials.
"SMI as an early sign of AD is further supported by evidence of reduced glucose metabolism in AD-related brain regions  . Moreover, amyloid positron emission tomography (PET) studies and cerebrospinal fluid (CSF) investigation provided evidence for an increased likelihood of amyloid deposition in individuals with SMI    . "
[Show abstract][Hide abstract] ABSTRACT: Elderly individuals with subjective memory impairment (SMI) report memory decline, but perform within the age-, gender-, and education-adjusted normal range on neuropsychological tests. Longitudinal studies indicate SMI as a risk factor or early sign of Alzheimer's disease (AD). There is increasing evidence from neuroimaging that at the group level, subjects with SMI display evidence of AD-related pathology. This study aimed to determine differences in cortical thickness between individuals with SMI and healthy control subjects (CO) using the FreeSurfer environment. 110 participants (41 SMI/69 CO) underwent structural 3D-T1 MR imaging. Cortical thickness values were compared between groups in predefined AD-related brain regions of the medial temporal lobe, namely the bilateral entorhinal cortex and bilateral parahippocampal cortex. Cortical thickness reduction was observed in the SMI group compared to controls in the left entorhinal cortex (p = 0.012). We interpret our findings as evidence of early AD-related brain changes in persons with SMI.
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