Elsevier

The Lancet Neurology

Volume 5, Issue 3, March 2006, Pages 228-234
The Lancet Neurology

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Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study

https://doi.org/10.1016/S1474-4422(06)70355-6Get rights and content

Summary

Background

Disease-modifying treatment strategies for Alzheimer's disease have led to an urgent need for biomarkers to identify the disease at a very early stage. Here, we assess the association between CSF biomarkers and incipient Alzheimer's in patients with mild cognitive impairment (MCI).

Methods

From a series of 180 consecutive patients with MCI, we assessed 137 who underwent successful lumbar puncture at baseline. Patients at risk of developing dementia were followed clinically for 4–6 years. Additionally, 39 healthy individuals, cognitively stable over 3 years, served as controls. We analysed CSF concentrations of β amyloid1–42 (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau181) using Luminex xMAP technology.

Findings

During follow-up, 57 (42%) patients with MCI developed Alzheimer's disease, 21 (15%) developed other forms of dementia, and 56 (41%) remained cognitively stable for 5·2 years (range 4·0–6·8). A combination of CSF T-tau and Aβ42 at baseline yielded a sensitivity of 95% and a specificity of 83% for detection of incipient AD in patients with MCI. The relative risk of progression to Alzheimer's disease was substantially increased in patients with MCI who had pathological concentrations of T-tau and Aβ42 at baseline (hazard ratio 17·7, p<0·0001). The association between pathological CSF and progression to Alzheimer's disease was much stronger than, and independent of, established risk factors including age, sex, education, APOE genotype, and plasma homocysteine. The combination of T-tau and Aβ42/P-tau181 ratio yielded closely similar results (sensitivity 95%, specificity 87%, hazard ratio 19·8).

Interpretation

Concentrations of T-tau, P-tau181, and Aβ42 in CSF are strongly associated with future development of Alzheimer's disease in patients with MCI.

Introduction

The prevalence of dementia doubles every 5 years from the age of 65 so that around 40% in the age-group 90–95 years are affected. With increasing life expectancy across the world, dementia is a rapidly growing socioeconomic and medical problem.1 Alzheimer's disease is the most common cause of dementia. The pathogenic process of Alzheimer's disease probably starts decades before the clinical onset of the disease.2 During this preclinical period there is a gradual loss of axons and neurons, and at a certain threshold the first symptoms, most often impaired episodic memory, appear. At this stage patients do not fulfil the criteria for dementia and may be diagnosed with mild cognitive impairment (MCI). However, MCI is a very common syndrome in elderly people and has a multitude of causes. Even though around 40–60% of patients with the syndrome develop Alzheimer's disease during the first 5 years, many have a stable form of memory impairment.3, 4 Moreover, early stages of vascular dementia or dementia with Lewy bodies, for example, can be preceded by MCI.4 Depression can also mimic the syndrome.

So far, there is no established method to predict progression to Alzheimer's disease in individuals with MCI. New tools to aid in the diagnostic work-up of individuals with MCI would be of fundamental public-health importance. Such methods would be of even greater significance if new drug candidates, such as β-sheet breakers, β-secretase inhibitors, and amyloid β1–42 (Aβ42) immunotherapy, prove to have disease-arresting effects. These types of drugs are likely to have the best efficacy in the early or even preclinical phase of the disease when the synaptic and neuronal loss has not become too widespread.5, 6 In fact, lack of tools to detect preclinical Alzheimer's disease has been suggested to be one of the main obstacles for the development of new treatments.7

Early studies indicated that CSF biomarkers could be useful for defining a subgroup of patients with MCI at especially high risk of developing Alzheimer's disease.5, 8, 9 However, the clinical follow-up in these studies has been short, generally only about 1–2 years.5, 8, 9 In view of the fact that each year MCI progresses to Alzheimer's disease in 8–15% of patients, a very extensive follow-up period (>4–5 years) would be needed to ascertain whether a patient with stable MCI really does not have incipient Alzheimer's disease.5 Moreover, when assessing the accuracy of a diagnostic test, the study should preferably include a consecutive series of patients from a relevant clinical population.10, 11, 12 However, the participants with MCI included in CSF studies have generally been highly selected—eg, by inclusion of only those patients who have MCI that progress to Alzheimer's disease and exclusion of individuals with MCI who have signs of cerebrovascular disease or depression.5 Furthermore, so far only one CSF study has investigated a consecutive series of patients with MCI, in which 57 participants were followed for an average of 2 years.9 In that study, only CSF total tau (T-tau) was analysed.

Two studies that used transgenic mice have shown that tau pathology is reversible only if intervention occurs early in the disease process.13, 14 Thus, there is a great need to find tools to identify incipient Alzheimer's disease in patients with MCI. We sought to assess the association between CSF biomarkers and incipient Alzheimer's disease in a clinically relevant, heterogeneous population of patients with MCI.

Section snippets

Participants

All patients who consulted the memory disorder clinic at Malmö University Hospital, Sweden, between July 1998, and June 2001, were screened for MCI. Most patients (75%) were referred to the clinic by family practitioners. This approach resulted in identification of 180 consecutive individuals with MCI, all of whom were assessed in the initial clinical study. At baseline, experienced physicians specialised in cognitive disorders undertook physical, neurological, and psychiatric examinations;

Results

A consecutive series of 180 patients with mild cognitive impairment was assessed. Patients were aged between 50 years and 86 years and 55% were women. At baseline, 137 (76%) patients with MCI underwent successful lumbar puncture, and were included in the study (table 1). CSF was analysed after the clinical follow-up was completed. Patients who did not undergo lumbar puncture did not differ from those who underwent the procedure with respect to diagnosis after clinical follow-up, baseline MMSE

Discussion

In this clinically based study, a combination of CSF T-tau and Aβ42 at baseline yielded a sensitivity of 95% and a specificity of 83% for detection of incipient Alzheimer's disease in patients with MCI. Combination of T-tau and the Aβ42/P-tau181 ratio28, 29 resulted in a slightly higher specificity. However, more studies are needed to establish which combination has the best performance, since the differences in our study were subtle. The association of all the different combinations of CSF

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