Cystatin C, a potential marker for cerebral microvascular compliance, is associated with white-matter hyperintensities progression

<div><p>Cerebral white matter hyperintensities (WMHs) are central MRI markers of the brain aging process, but the mechanisms for its progression remain unclear. In this study, we aimed to determine whether the baseline serum cystatin C level represented one mechanism underlying WMH progression, and whether it was associated with the long-term progression of cerebral WMH volume in MRI. 166 consecutive individuals who were ≥50 years of age and who underwent initial/follow-up MRI evaluations within an interval of 34–45 months were included. Serum cystatin C level, glomerular-filtration rate (GFR), and other laboratory parameters were measured at their initial evaluation and at the end of follow-up. Cerebrovascular risk factors, medications, and blood-pressure parameters were also reviewed. WMH progression rate was measured by subtracting WMH volume at baseline from that at the follow-up using volumetric analysis, divided by the MRI intervals. At baseline, WMH volume was 9.61±13.17 mL, mean GFR was 77.3±22.8 mL/min, and mean cystatin C level was 0.92±0.52 mg/L. After 37.9±3.4 months, the change in WMH volume was 3.64±6.85 mL, the progression rate of WMH volume was 1.18±2.28 mL/year, the mean ΔGFR was 2.4±7.9 mL/min, and the mean Δcystatin C was 0.03±0.34 mg/L. The progression rate of WMH volume was linearly associated with cystatin C level (B coefficient = 0.856; 95% confidence interval [CI] 0.174−1.538; <i>P</i> = 0.014), along with the baseline WMH volume (B = 0.039; 95% CI 0.019−0.059; <i>P</i><0.001), after adjusting for the conventional vascular risk factors, laboratory parameters, medication profiles, and GFR. Especially, patients with a baseline level of cystatin C ≥1.00 mg/L exhibited a much higher progression rate of WMH as compared with those with a baseline level of cystatin C <1.00 mg/L (1.60±1.91 mL/year vs. 0.82±1.63 mL/year, <i>P</i> = 0.010). We concluded that serum cystatin C level is independently associated with the long-term progression rate of the cerebral WMH volume. Therefore, serum cystatin C level might predict the progression of cerebral WMH.</p></div

Linear regression analyses for factors associated with white-matter hyperintensity progression rate.

<p>Linear regression analyses for factors associated with white-matter hyperintensity progression rate.</p

Clinical, laboratory, and white matter hyperintensity profiles of the study population.

<p>Clinical, laboratory, and white matter hyperintensity profiles of the study population.</p

Mean and standard deviations of the white-matter hyperintensity progression rate in the patients grouped per the categorical parameters.

<p>Mean and standard deviations of the white-matter hyperintensity progression rate in the patients grouped per the categorical parameters.</p

Effects of 8 or 14 days of treatment with photic stimulation and fluoxetine on the forced swim test in the CORT-induced mouse model of depression.

<p>The only-CORT group exhibited more immobility than the control group. Photic stimulation for 14 days but not 8 days resulted in a reduction in the immobility time compared with that of the only-CORT group. The fluoxetine-CORT group that received 14 days of treatment displayed a similar amount of immobility time compared with the only-CORT group. Notably, the co-administration of photic stimulation and fluoxetine for 8 days led to a reduction in immobility time compared with that shown by the only-CORT group. *comparison with control, **<i>p</i> < 0.01; ^#comparison with only-CORT group, ^#<i>p</i> < 0.05, Scheffe’s <i>post hoc</i> test.</p

Rhythmical Photic Stimulation at Alpha Frequencies Produces Antidepressant-Like Effects in a Mouse Model of Depression

<div><p>Current therapies for depression consist primarily of pharmacological agents, including antidepressants, and/or psychiatric counseling, such as psychotherapy. However, light therapy has recently begun to be considered as an effective tool for the treatment of the neuropsychiatric behaviors and symptoms of a variety of brain disorders or diseases, including depression. One methodology employed in light therapy involves flickering photic stimulation within a specific frequency range. The present study investigated whether flickering and flashing photic stimulation with light emitting diodes (LEDs) could improve depression-like behaviors in a corticosterone (CORT)-induced mouse model of depression. Additionally, the effects of the flickering and flashing lights on depressive behavior were compared with those of fluoxetine. Rhythmical flickering photic stimulation at alpha frequencies from 9–11 Hz clearly improved performance on behavioral tasks assessing anxiety, locomotor activity, social interaction, and despair. In contrast, fluoxetine treatment did not strongly improve behavioral performance during the same period compared with flickering photic stimulation. The present findings demonstrated that LED-derived flickering photic stimulation more rapidly improved behavioral outcomes in a CORT-induced mouse model of depression compared with fluoxetine. Thus, the present study suggests that rhythmical photic stimulation at alpha frequencies may aid in the improvement of the quality of life of patients with depression.</p></div

Distribution of the study population according to cystatin C values.

<p>Bar graphs denote the number of patients in each subgroup defined by intervals of cystatin C value. Sixty (24.2%) patients had a cystatin C level higher than 1.00 mg/L (dark blue bars). A normal distribution curve was also demonstrated.</p

Effects of 8 days of treatment with photic stimulation or fluoxetine on the elevated plus maze task in the CORT-induced mouse model of depression.

<p>The only-CORT and fluoxetine-CORT groups spent more and less time in the closed and open arms, respectively, than the control group. However, the photic-CORT group spent a similar amount of time in the open and closed arms as the control group, which indicates that the photic-CORT group had a normal level of anxiety. *comparison with control group, **<i>p</i> < 0.01; ^#comparison with only-CORT group, ^##<i>p</i> < 0.01, Scheffe’s <i>post hoc</i> test.</p

The effect of dim light at night on cerebral hemodynamic oscillations during sleep: A near-infrared spectroscopy study

<p>Recent studies have reported that dim light at night (dLAN) is associated with risks of cardiovascular complications, such as hypertension and carotid atherosclerosis; however, little is known about the underlying mechanism. Here, we evaluated the effect of dLAN on the cerebrovascular system by analyzing cerebral hemodynamic oscillations using near-infrared spectroscopy (NIRS). Fourteen healthy male subjects underwent polysomnography coupled with cerebral NIRS. The data collected during sleep with dim light (10 lux) were compared with those collected during sleep under the control dark conditions for the sleep structure, cerebral hemodynamic oscillations, heart rate variability (HRV), and their electroencephalographic (EEG) power spectrum. Power spectral analysis was applied to oxy-hemoglobin concentrations calculated from the NIRS signal. Spectral densities over endothelial very-low-frequency oscillations (VLFOs) (0.003–0.02 Hz), neurogenic VLFOs (0.02–0.04 Hz), myogenic low-frequency oscillations (LFOs) (0.04–0.15 Hz), and total LFOs (0.003–0.15 Hz) were obtained for each sleep stage. The polysomnographic data revealed an increase in the N2 stage under the dLAN conditions. The spectral analysis of cerebral hemodynamics showed that the total LFOs increased significantly during slow-wave sleep (SWS) and decreased during rapid eye movement (REM) sleep. Specifically, endothelial (median of normalized value, 0.46 vs. 0.72, <i>p</i> = 0.019) and neurogenic (median, 0.58 vs. 0.84, <i>p</i> = 0.019) VLFOs were enhanced during SWS, whereas endothelial VLFOs (median, 1.93 vs. 1.47, <i>p</i> = 0.030) were attenuated during REM sleep. HRV analysis exhibited altered spectral densities during SWS induced by dLAN, including an increase in very-low-frequency and decreases in low-frequency and high-frequency ranges. In the EEG power spectral analysis, no significant difference was detected between the control and dLAN conditions. In conclusion, dLAN can disturb cerebral hemodynamics via the endothelial and autonomic systems without cortical involvement, predominantly during SWS, which might represent an underlying mechanism of the increased cerebrovascular risk associated with light exposure during sleep.</p

Effects of 10–12 days of treatment with photic stimulation or fluoxetine in the open-field and social interaction tasks in the CORT-induced mouse model of depression.

<p>(A–B) Open-field task: (A) Total distance moved in the open-field box, and (B) time spent in the center area of the open-field box. The photic-CORT and control groups exhibited similar distances moved and amounts of time in the center, whereas the only-CORT and fluoxetine-CORT groups showed a reduction in total distance moved and time spent in the center area compared with the control group. (C) Social interaction task: the photic-CORT and fluoxetine-CORT groups displayed similar interaction times compared with the control group, but the only-CORT group showed a reduced amount of interaction time compared with the other groups. *comparison with control, *<i>p</i> < 0.05, **<i>p</i> < 0.01; ^#comparison with only-CORT group, ^#<i>p</i> < 0.05, ^##<i>p</i> < 0.01, Scheffe’s <i>post hoc</i> test.</p