The development of late-onset Alzheimer's disease is believed to be influenced by genetic, socioeconomic, and lifestyle factors. Recently, converging research in animal and human studies has found that beta-amyloid (Aβ) levels in cerebrospinal fluid are modulated by sleep-wake cycles. This raises the possibility that chronic sleep loss causes brain amyloid accumulation over time and leads to the development of Alzheimer's disease. The observation that circadian rhythm modulates Aβ levels has not yet been replicated by other groups, and subject selection and methodologies are potential explanations for this. While acute suppression of sleep may raise Aβ levels, it is not known whether chronic sleep loss has the same effect. It is conceivable that altered circadian rhythms are a manifestation of a disrupted sleep network because of preclinical disease, as has been observed in other neurodegenerative disorders. The findings that circadian variation in Aβ levels in cerebrospinal fluid is a direct result of sleep-wake cycles and that altering normal rhythms increases the risk for brain amyloid accumulation need to be replicated in larger cohorts. Prospective studies are needed to decipher whether circadian rhythm dysfunction is a cause, or a result of, amyloid accumulation.

Objective

To determine whether cerebrospinal fluid (CSF) biomarkers for Alzheimer disease fluctuate significantly over time in a cohort of older, mildly symptomatic individuals.

Design

Biomarker validation in a clinical cohort.

Setting

University hospital inpatient unit.

Participants

Ten patients admitted for CSF drainage for diagnostic purposes.

Main Outcome Measures

The CSF levels of Aβ1–40, Aβ1–42, tau, and phosphorylated tau on threonine 181 (p-tau181) were measured every 6 hours for 24 or 36 hours.

Results

The mean coefficient of variation values for each biomarker assessed in our 10 patients were 5.5% (95% CI, 3.8%–10.0%) for Aβ1–42, 12.2% (9.0%–24.2%) for Aβ1–40, 8.2% (5.7%–15.1%) for total tau, and 11.9% (8.5%–23.0%) for p-tau181. These values are only slightly higher than the variability in the assay. In addition, no significant circadian fluctuation in any Alzheimer disease biomarker was observed given the limitations of our sampling frequency.

Conclusion

In a cohort of elderly patients, little fluctuation in the levels of important Alzheimer disease biomarkers in lumbar CSF is seen as a function of time.

Objectives

To examine the effect of specific “CSF profiles” on the rate of cognitive decline, disease progression, and risk of conversion to Alzheimer's disease (AD) dementia in patients with amnestic mild cognitive impairment (MCI).

Design

Total tau (t-tau), tau phosphorylated at threonine 181 (p-tau181), and β-amyloid 1-42 peptide (Aβ42) were immunoassayed in CSF samples obtained from MCI patients enrolled in the Alzheimer's Disease Neuroimaging Initiative. Patients were then stratified by “CSF profiles”: (1) normal t-tau and Aβ42 levels (i.e., normal–t-tauAβ42), (2) normal t-tau but abnormal Aβ42 (i.e., abnormal–Aβ42), (3) abnormal t-tau but normal Aβ42 (i.e., abnormal–t-tau), and (4) abnormal t-tau and Aβ42 (i.e., abnormal–t-tauAβ42).

Setting

Fifty-eight sites in the US and Canada.

Participants

One hundred ninety-five MCI patients.

Main Outcome Measures

A composite cognitive measure, the CDR-Sum of Boxes, and conversion to AD.

Results

MCI patients with a CSF profile of abnormal–Aβ42 or abnormal–t-tauAβ42 experienced a faster rate of decline on the composite cognitive measure and the CDR-Sum of Boxes compared to those with normal–t-tauAβ42. They also had a greater risk of converting to AD relative to the normal–t-tauAβ42 group. In contrast, those with a CSF profile of abnormal–t-tau did not differ from the normal–t-tauAβ42 group on any outcome. These findings were generally replicated when the sample was reclassified by patterns of p-tau181 and Aβ42 abnormalities.

Conclusions

β-amyloid abnormalities, but not tau alterations, are associated with cognitive deterioration, disease progression, and increased risk of conversion to AD dementia in patients with MCI. Patients with abnormal levels of Aβ42 may be prime targets for drug treatment and clinical trials in MCI.

In cultured spinal neurons, NMDA receptors are absent from excitatory synapses under basal conditions, but can be made to appear at excitatory synapses following blockade of excitatory synaptic activity. The activity dependent synaptic localization of NMDA receptors is critically dependent on both the gradual, global accumulation of the NR2A and NR2B subunits and on a rapid, surface redistribution phase that is primed by the accumulation of NR2A and NR2B and inhibited by synaptic activity. Global changes in NR2A and NR2B accumulation and heterogeneous increases in synaptic NMDA receptor localization can also result from inhibitors of proteasomal processing, from manipulations of proteasomal subunit composition and from media conditioned by neurons undergoing synaptic scaling. While proteasomal processing is a mechanism shared with AMPA receptor scaling in cultured spinal neurons, diffusible factors, heterogeneity, and a rapid surface redistribution phase appear to be unique to activity dependent synaptic NMDA receptor localization.