Hourly analysis of cerebrospinal fluid glucose shows large diurnal fluctuations.

Cerebrospinal fluid analysis is important in the diagnostics of many neurological disorders. Since the influence of food intake on the cerebrospinal fluid glucose concentration and the cerebrospinal fluid/plasma glucose ratio is largely unknown, we studied fluctuations in these parameters in healthy adult volunteers during a period of 36 h. Our observations show large physiological fluctuations of cerebrospinal fluid glucose and the cerebrospinal fluid/plasma glucose ratio, and their relation to food intake. These findings provide novel insights into the physiology of cerebral processes dependent on glucose levels such as energy formation (e.g. glycolysis), enzymatic reactions (e.g. glycosylation), and non-enzymatic reactions (e.g. advanced endproduct glycation).

An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-ß concentrations collected by lumbar puncture and indwelling lumbar catheter.

INTRODUCTION: Amyloid-ß (Aß) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Aß fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Aß variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF Aß concentrations over time. METHODS: Grouped analysis of CSF Aß levels from multiple industry and academic groups collected by either lumbar puncture (n=83) or indwelling lumbar catheter (n=178). Participants were either placebo or untreated subjects from clinical drug trials or observational studies. Participants had CSF collected by lumbar puncture or lumbar catheter for quantitation of Aß concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for Aß40 and Aß42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of Aß concentrations over time. RESULTS: Analysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of Aß40 and Aß42 as well as an Aß diurnal pattern in all of the sponsors' studies. In contrast, Aß concentrations from CSF samples collected at two time points by lumbar puncture showed no significant differences. Repeated measures analysis of variance found that only time and draw frequency were significantly associated with the slope of linear rise in Aß40 and Aß42 concentrations during the first 6 hours of collection. CONCLUSIONS: Based on our findings, we recommend minimizing the frequency of CSF draws in studies measuring Aß levels and keeping the frequency standardized between experimental groups. The Aß diurnal pattern was noted in all sponsors' studies and was not an artifact of study design. Averaging Aß concentrations at each time point is recommended to minimize the effect of individual variability. Indwelling lumbar catheters are an invaluable research tool for following changes in CSF Aß over 24-48 hours, but factors affecting Aß concentration such as linear rise and diurnal variation need to be accounted for in planning study designs.

Reciprocal interactions between sleep, circadian rhythms and Alzheimer's disease: focus on the role of hypocretin and melatonin.

AD, sleep and circadian rhythm physiology display an intricate relationship. On the one hand, AD pathology leads to sleep and circadian disturbances, with a clear negative influence on quality of life. On the other hand, there is increasing evidence that both sleep and circadian regulating systems exert an influence on AD pathology. In this review we describe the impairments of both sleep regulating systems and circadian rhythms in AD and their link to clinical symptoms, as this may increase knowledge on appropriate diagnosis and adequate treatment of sleep problems in AD. Furthermore we discuss how sleep regulating systems, and especially neurotransmitters such as melatonin and hypocretin, may affect AD pathophysiology, as this may provide a role for lack of sleep and circadian rhythm deterioration in the onset of AD.

Association between hypocretin-1 and amyloid-ß42 cerebrospinal fluid levels in Alzheimer's disease and healthy controls.

Alzheimer's disease is associated with sleep disorders. Recently, animal studies demonstrated a link between hypocretin, a sleep-regulation neurotransmitter, and AD pathology. In this study, we investigated the circadian rhythm of hypocretin-1 in Alzheimer's Disease (AD) patients and controls. Moreover, we assessed the relation between CSF hypocretin-1 and amyloid-ß. A continuous CSF sampling study via indwelling intrathecal catheter was performed to collect hourly CSF samples of six patients with AD (59-85 yrs, MMSE 16-26) and six healthy volunteers (64-77 yrs). CSF hypocretin-1 and Aß42 concentrations were determined at 8 individual time points over 24 hours. A circadian pattern was assessed by fitting a 24 hour sine curve to the hypocretin-1 data using mixed model analysis. Clinical diagnosis and Aß42 were entered into the model as time invariant covariates to determine differences between AD and controls, and correlate Aß42 to hypocretin-1 levels. A hypocretin-1 circadian rhythm with an amplitude of 11.5 pg/ml was found in clinical AD patients, which did not differ from the control group (7.15 pg/ml). Lower mean CSF Aß42 levels were related to lower hypocretin-1 levels; 1.6 pg/ml hypocretin-1 per 10 pg/ml Aß42 (p=0.03), and a higher amplitude of the hypocretin-1 circadian rhythm (0.4 pg/ml, p=0.03). CSF hypocretin-1 has a circadian rhythm for which we could show no difference between AD and controls. However, the association between mean Aß42 levels and mean hypocretin-1 levels and amplitude may suggest a relationship between AD pathology and hypocretin disturbance, which could hold possibilities for treatment of AD related sleep disorders.

Hourly variability of cerebrospinal fluid biomarkers in Alzheimer's disease subjects and healthy older volunteers.

Large hour-to-hour variability has previously been demonstrated in the cerebrospinal fluid (CSF) concentrations of Alzheimer's disease (AD) biomarkers amyloid ß(42) (Aß(42)) and Aß(40) in healthy younger subjects. We investigated the within-subject variability over 36 hours in CSF Aß and tau proteins, in older subjects and AD patients. Six patients with mild stage AD (59-85 years, Mini Mental State Examination (MMSE) 16-26) and 6 healthy older volunteers (64-77 years) received an intrathecal catheter from which, during 36 hours, each hour 6 mL of CSF was drawn. Concentrations of Aß(42), Aß(40), total tau, and phosphorylated tau were determined and the variability was analyzed. Within-subject variability within 3-hour periods was assessed as the coefficient of variation, which was comparable for these 4 biomarkers in controls (4.2%-4.6%) and AD (3.1%-5.8%). Variability over 12 hour periods was 5.3% to 9.5%. These findings suggest that CSF biomarker variability is relatively low in healthy older controls and AD patients. Furthermore, continuous sampling of CSF proved to be a useful and robust method, which may also be used to investigate AD pathogenesis and to evaluate pharmacotherapeutic interventions.

CSF α-synuclein concentrations do not fluctuate over hours and are not correlated to amyloid ß in humans.

Reports on the value of cerebrospinal fluid (CSF) α-synuclein as a biomarker for dementia with Lewy bodies and Parkinson disease are contradicting. This may be explained by fluctuating CSF α-synuclein concentrations over time. Such fluctuations have been suggested for CSF amyloid ß concentrations. Furthermore, a physiological relationship between α-synuclein and amyloid ß has been suggested based on in vitro research. We performed repeated CSF sampling in healthy elderly and AD patients and showed that sinusoidal fluctuations in CSF α-synuclein concentrations were not present. Furthermore, we did not find evidence for an interaction between amyloid ß and α-synuclein concentrations in CSF.

Cerebrospinal Fluid Biomarkers in Diagnosing Alzheimer's Disease in Clinical Practice: An Illustration with 3 Case Reports.

Analysis of the brain specific biomarkers amyloid beta(42) (Abeta(42)) and total tau (t-tau) protein in cerebrospinal fluid (CSF) has a sensitivity and specificity of more than 85% for differentiating Alzheimer's Disease (AD) from non-demented controls. International guidelines are contradictory in their advice on the use of CSF biomarkers in AD diagnostics, resulting in a lack of consistency in clinical practice. We present three case reports that illustrate clinical practice according to the Dutch and European guidelines and portray the value of CSF biomarker analysis as an add-on diagnostic to the standard diagnostic workup for AD.