Bright light improves sleep in patients with Parkinson's disease: possible role of circadian restoration.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Among the most common manifestations of PD are sleep problems, which are coupled with the adverse effects of dopaminergic therapies (DT). A non-pharmacological solution for these sleep problems has been sought to avoid additional pharmacological intervention. Here, we show that bright light therapy (BLT) is effective for improving sleep in Japanese PD patients receiving DT. Furthermore, experimental evaluation of peripheral clock gene expression rhythms revealed that most PD patients receiving DT who experienced improved sleep following BLT showed a circadian phase shift, indicating the existence of a correlation between circadian modulation and sleep improvement. Conversely, this result indicates that sleep problems in PD patients receiving DT may arise at least in part as a result of circadian dysfunction. Indeed, we found that chronic dopaminergic stimulation induced a rapid attenuation of autonomous oscillations of clock gene expression in ex vivo cultured mouse suprachiasmatic nucleus (SCN) at the single neuron level. In conclusion, BLT is a promising medical treatment for improving sleep in PD patients receiving DT. This BLT-induced improvement may be due to the restoration of circadian function.

Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit.

Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress-gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-of-hypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis.

Magnetic resonance spectroscopic study of Alzheimer's disease and frontotemporal dementia/Pick complex.

Disease-specific metabolic changes in Alzheimer's disease and frontotemporal dementia/Pick complex were examined by proton magnetic resonance spectroscopy at 3.0 T. Spectra were acquired from posterior and anterior cingulate cortices and the parieto-occipital and frontal white matter. This study included eight Alzheimer's disease patients, 10 frontotemporal dementia/Pick complex patients and 14 healthy volunteers. N-acetylaspartate/creatine+phosphocreatine ratio was reduced in the posterior cingulate cortex in the Alzheimer's disease and frontotemporal dementia/Pick complex patients. The Alzheimer's disease patients, however, showed a posterior dominant decrease, whereas the frontotemporal dementia/Pick complex patients showed a frontal predominant decrease. These different distributions of metabolic changes may represent the underlying pathological processes in each disease. Our standardized protocol of proton magnetic resonance spectroscopy measurement may be helpful in differentiating these dementia subtypes.

Determination of transverse relaxation rate for estimating iron deposits in central nervous system.

To determine the amount of iron deposits in the basal ganglia, we examined 13 healthy volunteers with a 1.5 T MRI system using three transverse relaxation rates measured with two sequences. The transverse relaxation rates comprise the reversible contribution (R2') and irreversible contribution (R2) to a phase-reversal 180 degrees -pulse sequence. The transverse relaxation rates with the estimated iron indicated that both R2 and R2' had a robust relationship with brain iron level as determined from published post mortem data. This was the case only when the analyses are limited to the subcortical gray matter regions, however. R2' was affected by macroscopic magnetic field inhomogeneity arising from the skull bases, so that it was less robust for estimating the amount of iron deposits in the basal ganglia.

The efficacy of trientine or ascorbate alone compared to that of the combined treatment with these two agents in familial amyotrophic lateral sclerosis model mice.

One of the hypotheses regarding the pathogenesis of familial ALS (FALS) is a copper-mediated oxidative toxicity derived from the mutant Cu, Zn-superoxide dismutase (SOD1). We have previously demonstrated the efficacy of the combined treatment with a copper chelator (trientine) and an antioxidant (ascorbate) on the disease expression of the FALS-linked mutated SOD1 transgenic mice. Here, we investigated the efficacy of trientine or ascorbate alone on FALS mice when administered before or after the onset of the disease. The mice with a high dose of trientine or ascorbate administered before the onset survived significantly longer than the control. In the combined treatment with a high dose of trientine and ascorbate initiated before the onset, survival lengthened and the motor function of the mice remained more significantly than the control. None of the treatments affected the mean age of the onset, and none of the agents administered after the onset prolonged survival. These findings suggest that better outcomes may be expected by the administration of these agents at the preonset stage of the disease, and the combination of the agents acting on different sites might be useful in preserving the motor performance in FALS.