Association Between Late-Onset Leukoencephalopathy With Vanishing White Matter and Compound Heterozygous EIF2B5 Gene Mutations: A Case Report and Review of the Literature.

Leukoencephalopathy with vanishing white matter (LVWM) is an autosomal recessive disease. Ovarioleukodystrophy is defined as LVWM in females showing signs or symptoms of gradual ovarian failure. We present a 38-year-old female with ovarioleukodystrophy who showed status epilepticus, gait instability, slurred speech, abdominal tendon hyperreflexia, and ovarian failure. Abnormal EEG, characteristic magnetic resonance, and unreported EIF2B5 compound heterozygous mutations [c.1016G>A (p.R339Q) and c.1157G>A (p.G386D)] were found. Furthermore, the present report summarizes 20 female patients with adult-onset ovarioleukodystrophy and EIF2B5 gene mutations. In conclusion, a new genetic locus for LVWM was discovered. Compared with previous cases, mutations at different EIF2B5 sites might have different clinical manifestations and obvious clinical heterogeneity.

Different patterns of functional and structural alterations of hippocampal sub-regions in subcortical vascular mild cognitive impairment with and without depression symptoms.

In addition to cognitive impairments, depression symptoms were reported in subcortical vascular mild cognitive impairment. Although hippocampal alterations were associated with cognitive decline in subcortical vascular mild cognitive impairment, the neural mechanism underlying depression symptoms remains unclear. Thus, a cohort of 18 patients with depression symptoms, 17 patients without depression symptoms, and 23 normal controls was used. Functionally, significantly altered resting-state functional connectivity between hippocampal emotional sub-region and right posterior cingulate cortex, between hippocampal cognitive sub-region and right inferior parietal gyrus and between hippocampal perceptual sub-region and left inferior temporal gyrus were identified among three groups. Structurally, significantly altered structural associations between hippocampal emotional sub-region and 6 frontal regions/right pole part of superior temporal gyrus/right inferior occipital gyrus, between hippocampal cognitive sub-region and right orbital part of inferior frontal gyrus /right anterior cingulate cortex, and between hippocampal perceptual and right orbital part of inferior frontal gyrus / left inferior temporal gyrus / left thalamus were identified among the three groups. Further analyses also showed correlations between functional connectivity and depression symptoms and/or cognitive impairments of patients. Together, these results showed different patterns of functional and structural alterations of the hippocampal sub-regions in the subcortical vascular mild cognitive impairment with and without depression, which might be specially associated with the depression symptoms and cognitive impairments in these patients.

Cortical Alterations Are Associated with Depression in Subcortical Vascular Mild Cognitive Impairment Revealed by Surface-Based Morphometry.

BACKGROUND: Late-life depression often coexists with vascular cognitive impairment and affects the quality of life for elders. However, little is known about cortical morphometric interactions between subcortical vascular mild cognitive impairment (svMCI) and concomitant mild depressive symptoms at the early stage. OBJECTIVE: We aimed to investigate cortical alterations of svMCI with and without depressive symptoms and determine whether these parameters are associated with depression symptoms and/or cognitive impairments. METHODS: Surface based morphometry was performed on 18 svMCI patients with depressive symptoms (svMCI + D), 16 svMCI patients without depressive symptoms (svMCI-D), and 23 normal controls (NC). RESULTS: Compared to NC, both svMCI + D and svMCI-D patients exhibited significantly decreased surface area (SA) in many cortical areas. Interestingly, svMCI + D patients showed significantly increased rather than decreased SA in right lateral occipital gyrus (LOG.R), and a consistent trend of increased SA in these areas compared to svMCI-D. In addition, the svMCI + D showed increased gray matter volume of left pericalcarine (periCAL.L) than svMCI-D, whereas svMCI-D showed decreased gray matter volume of periCAL.L than NC. Further correlation analyses revealed that the SA of left superior temporal gyrus (STG.L) and right lateral orbital part of frontal gyrus (lorbFG.R) were significantly correlated with Hamilton depression rating scale of svMCI + D. CONCLUSION: In conclusion, these results extend our insight into svMCI and add weight to reevaluation of concomitant early stage depressive symptoms. Moreover, we suggest that LOG.R∖periCAL.L∖STG.L∖lorbFG.R might serve as sensitive and trait-dependent biomarkers to detect concomitant depressive symptoms in svMCI patients.

The Neuroprotective Effects of Danggui-Shaoyao San on Vascular Cognitive Impairment: Involvement of the Role of the Low-Density Lipoprotein Receptor-Related Protein.

Effective drugs for treating dementia are still rare. Danggui-Shaoyao San (DSS), a traditional Chinese medicine, has been widely used in oriental countries for the treatment of various gynecological diseases. Many studies reported that DSS could ameliorate cognitive impairment. In this study, we aimed to investigate the underlying mechanism of DSS on vascular cognitive impairment (VCI) rats. Chronic cerebral hypoperfusion (CCH) is one of the main causes of VCI. CCH resulted in a chain of pathological process, including neuroinflammation, neuronal apoptosis, and oxidative stress. The most widely used animal model of VCI is permanent bilateral common carotid artery occlusion in rats. In this research, we determined whether DSS attenuated cognitive impairment by targeting I kappa B kinase (IKK)/nuclear factor of kappa B (NF-κB) signal pathway in VCI rats. Morris water maze and fear conditioning tests results indicated that DSS [7.2 g/(kg·d)] could improve learning and memory ability in VCI rats. We also found DSS significantly elevated the levels of low-density lipoprotein receptor-related protein 1 (LRP1) in the brain of VCI rats and this might indirectly target the IKK/NF-κB signal pathway to exert inhibitory effect on neuroinflammation, neuronal apoptosis, and oxidative stress in VCI rats. The present researches indicated that DSS might attenuate cognitive impairment by targeting IKK/NF-κB signal pathway in VCI rats and DSS might be a promising agent on VCI.

Alterations of White Matter Microstructure in Subcortical Vascular Mild Cognitive Impairment with and without Depressive Symptoms.

BACKGROUND: Depressive symptoms were thought to increase the risk of vascular dementia. Previous studies reported widespread white matter damages in the subcortical vascular mild cognitive impairment (svMCI), but little is known about the mechanism of depressive symptoms in svMCI. OBJECTIVE: In the current study, we aim to explore the white matter microstructural alterations in svMCI with depressive symptoms, and their associations with clinical measurements. METHODS: Fifty-eight subjects including 18 svMCI with depression (svMCI+D), 17 svMCI without depression (svMCI-D), and 23 normal controls (NC) were included in the study. Voxel-based analyses were performed on fractional anisotropy (FA) and mean diffusivity (MD). RESULTS: Compared to NC, both svMCI groups showed decreased FA in the bilateral insula and the left precentral gyrus, and increased MD in the cerebellum. Compared to svMCI-D, svMCI+D showed increased FA in left precentral gyrus. Moreover, svMCI+D showed significant correlation between the increased MD in the cerebellum and the Hamilton Depression Rating Scale (HAMD) scores. CONCLUSION: Our findings of white matter alterations might be associated with executive function and memory performance in the svMCI patients. Moreover, the structural alterations in the cerebellum might underlie the mechanism of depressive symptoms in svMCI patients.

[Effect of "Yinqi Guiyuan" needling on primary insomnia].

OBJECTIVE: To observe the clinical effect of "Yinqi Guiyuan" needling in the treatment of primary insomnia. METHODS: A total of 79 primary insomnia outpatients were randomly divided into treatment group (n=40) and control group (n=39). The patients in the control group were given oral Estazolam tablets once a day, for successive 4 weeks. For patients of the treatment group, Zhongwan (CV12), Xiawan (CV10), Qihai (CV6), Guanyuan (CV4), Baihui (GV20), etc., were punctured with filiform needles for 30 min. The treatment was conducted three times per week for 4 successive weeks. The sleep quality (sleeping quality, falling asleep time, sleep duration, sleep efficiency, sleep disorders, hypnotic and daytime dysfunction, 0 to 21 points) was evaluated by using Pittsburgh Sleep Quality Index (PSQI). The severity of insomnia (self-perception, sleep satisfaction, daytime function damage, sensibility change, and concern for sleep problems, 0 to 28 points) was assessed using insomnia severity index (ISI) score. The therapeutic effect was evaluated according to the PSQI score reduction rate = (pre-treatment PSQI score-post-treatment PSQI score)/pre-treatment PSQI score ×100%. RESULTS: After treatment, the total score of PSQI, ISI and the score of each item were all significantly reduced in the two groups relevant to their own pre-treatment (P<0.05). The total score, and scores of hypnotic and daytime dysfunction were significantly lower in the treatment group than in the control group (P<0.05). Of the 40 and 39 cases in the treatment and control groups, 5 (12.50%) and 4 (10.25%) were cured, 20 (50.00%) and 18 (46.15%) experienced marked improvement, 12 (30.00%) and 13 (33.33%) were effective, and 3 (7.50%) and 4 (10.25%) ineffective, with the total effective rate being 92.50% and 89.74%, respectively. No significant difference was found between the two groups in the effective rate (P>0.05). CONCLUSION: "Yinqi Guiyuan" needling and Estazolam are comparable in treatment primary insomnia, and the former is superior to the latter in avoiding hypnotic drug use and in improving daytime function.

Structural and Functional Disruptions in Subcortical Vascular Mild Cognitive Impairment With and Without Depressive Symptoms.

Many previous studies have revealed structural and functional abnormalities in patients with the subcortical vascular mild cognitive impairment (svMCI). Although depression symptoms were suggested to serve as a potential marker of conversion to dementia in patients with svMCI, whether these disruptions or other new findings will be identified in the svMCI comorbid with depression symptoms has not been established. In the current study, we combined voxel-based morphometry (VBM) and the resting-state functional magnetic resonance imaging (fMRI) to investigate the structural and functional disruptions in the svMCI with and without depression symptoms using a cohort of 18 svMCI with depression symptoms (svMCI+D), 17 svMCI without depression symptoms (svMCI-D), and 23 normal controls (NC). As a result, we identified significantly decreased gray matter density in the left parahippocampus (ParaHIPP.L), the right hippocampus (HIPP.R), and the right middle cingulate cortex (MCC.R) in both svMCI+D and svMCI-D compared to NC. Most importantly, we also identified increased gray matter density in the MCC.R accompanied by increased resting-state functional connectivity (RSFC) with right parahippocampus (ParaHIPP.R) in the svMCI+D compared to svMCI-D. Moreover, the gray matter density of MCC.R and ParaHIPP.L was correlated with cognitive impairments and depression symptoms in the svMCI, respectively. In conclusion, these results extended previous studies and added weight to considerations of depression symptoms in the svMCI. Moreover, we suggested that a processing loop associated with HIPP, ParaHIPP, and MCC might underlie the mechanism of depression symptoms in the svMCI.

Senkyunolide A protects neural cells against corticosterone-induced apoptosis by modulating protein phosphatase 2A and α-synuclein signaling.

BACKGROUND: Depression is characterized by a pathological injury to the hippocampal neurons. Senkyunolide A (SenA) is one of the major active components of Dan-zhi-xiao-yao-san, which is widely used in the treatment of depression-related disorders. MATERIALS AND METHODS: In the present study, it was hypothesized that the antidepressant effect of Dan-zhi-xiao-yao-san depended on the function of SenA and the authors attempted to reveal the molecular mechanism associated with the treatment. An in vitro depression model was induced using corticosterone (Cort), and the effect of SenA on the cell viability, apoptosis, and protein phosphatase 2A/α-synuclein (PP2A/α-syn) signaling was detected. To validate the mechanism driving the therapeutic effect of SenA, activity of PP2A and α-syn was modulated and the effect on neural cells was evaluated. RESULTS: The results showed that SenA protects Cort-induced cell apoptosis in PC12 cells. In addition, SenA increased Cort-induced reduction of PP2A activity, while it decreased the expression of p-PP2A, α-syn, and p-α-syn (Ser129). Further, modulation of PP2A activity with specific inhibitor okadaic acid (OA) increased Cort-induced cell apoptosis, while PP2A activator D-erythro-sphingosine (SPH) exhibited an opposite effect. The neuroprotective effects of SenA on neural cells also depended on inhibition of α-syn function, the regulation of which would influence the activity of PP2A in a negative loop. CONCLUSION: Collectively, the results suggested that the neuroprotective effects of SenA were exerted by modulating activities of PP2A activities and α-syn. The findings partially explained the mechanism associated with the neuroprotective effect of SenA.

Correction: Neuroprotective effects of bajijiasu against cognitive impairment induced by amyloid-ß in APP/PS1 mice.

[This corrects the article DOI: 10.18632/oncotarget.21515.].

Multiple intracranial lesions as the unusual imaging features of Hashimoto's encephalopathy: A case report.

RATIONALE: Hashimoto's encephalopathy (HE) is associated with autoimmune thyroid disease and is complex, diverse, and easily misdiagnosed. However, if HE is diagnosed and treated in a timely manner, an optimal prognosis may be achieved. PATIENT CONCERNS: We presented a case of a 63-year-old female patient with paroxysmal dizziness, unsteady gait, emotion apathy, progressive cognitive impairment, and unusual magnetic resonance imaging (MRI) findings. DIAGNOSES: After suffering for almost 8 years, the patient was diagnosed with HE based on clinical manifestation, abnormal electroencephalogram, unusual MRI findings, sensitivity to cortisol treatment, and characteristic high antithyroid peroxidase antibody (TpoAb) titer. INTERVENTIONS: The patient continued regular glucocorticoids therapy after intravenous methylprednisolone pulse therapy, neurotrophic drugs, traditional Chinese medicine and rehabilitation to relieve hypermyotonia and cognitive impairment. OUTCOMES: After combined treatment, the patient's symptoms, electroencephalogram (EEG), MRI, and the TpoAb titer gradually improved. However, the patient had to stop glucocorticoids treatment because of severe osteoporosis, fractures and other adverse reactions. Her symptoms fluctuated, and her TpoAb titer increased again. LESSONS: HE may cause highly heterogeneous clinical features, particularly MRI findings. Withdrawal of the systematic glucocorticoids treatment can lead to varied outcomes in these patients.

The Mechanisms of Bushen-Yizhi Formula as a Therapeutic Agent against Alzheimer's Disease.

Bushen-Yizhi prescription (BSYZ) has been an effective traditional Chinese medicine (TCM) prescription in treating Alzheimer's disease (AD) for hundreds of years. However, the underlying mechanisms have not been fully elucidated yet. In this work, a systems pharmacology approach was developed to reveal the underlying molecular mechanisms of BSYZ in treating AD. First, we obtained 329 candidate compounds of BSYZ by in silico ADME/T filter analysis and 138 AD-related targets were predicted by our in-house WEGA algorithm via mapping predicted targets into AD-related proteins. In addition, we elucidated the mechanisms of BSYZ action on AD through multiple network analysis, including compound-target network analysis and target-function network analysis. Furthermore, several modules regulated by BSYZ were incorporated into AD-related pathways to uncover the therapeutic mechanisms of this prescription in AD treatment. Finally, further verification experiments also demonstrated the therapeutic effects of BSYZ on cognitive dysfunction in APP/PS1 mice, which was possibly via regulating amyloid-ß metabolism and suppressing neuronal apoptosis. In conclusion, we provide an integrative systems pharmacology approach to illustrate the underlying therapeutic mechanisms of BSYZ formula action on AD.

Neuroprotective effects of bajijiasu against cognitive impairment induced by amyloid-ß in APP/PS1 mice.

Alzheimer's disease (AD) is a progressive neurological degenerative disease. The main clinical manifestations of AD include progressive cognitive impairment and alteration of personality. Senile plaques, neuroinflammation, and destruction of synapse structure stability are the main pathological features of AD. Bajijiasu(BJJS) is extracted from Morinda Officinalis, a Chinese herb. In this study, we explored the effect of BJJS on AD from many aspects in APPswe/PSEN1ΔE9 (APP/PS1) double transgenic mice. The Morris water maze and novel object recognition tests results showed that BJJS could significantly improve the learning and memory abilities in APP/PS1 mice. BJJS treatment increased the level of insulin degradation enzyme (IDE) and neprilysin (NEP) and decreased the level of ß-site app cleaving enzyme 1(BACE1) in the brain of APP/PS1 mice. BJJS-treated APP/PS1 mice appeared to have reductions of Aß deposition and senile plaques, and showed higher levels of neurotrophic factors in the brain. We also found that BJJS had an inhibitory function on neuroinflammation in APP/PS1 mice. In addition, the synapse structure relevant proteins were elevated in the brain of BJJS-treated APP/PS1 mice. The present results indicated that BJJS could attenuate cognitive impairment via ameliorating the AD-related pathological alterations in APP/PS1 mice. These findings suggest that BJJS may be a potential therapeutic strategy in Alzheimer's disease.

Bipolar II disorder as the initial presentation of CADASIL: an underdiagnosed manifestation.

Mood disturbances have been documented in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The highly varied morbidity indicates that the affective symptoms in CADASIL have not been cataloged systematically, leading to ineffective treatment, affecting the patients' quality of life, and possibly resulting in suicide. We present a case of CADASIL with bipolar II disorder as the first manifestation. A middle-aged female reported recurrent depressive episodes and appeared treatment resistant to adequate dosages and durations of antidepressants. Following a structured psychiatric interview and neuropsychological assessment, a past episode of hypomania was identified. Added treatment with sodium valproate alleviated most symptoms. Considering late-onset bipolar disorder with unexplained decline in cognition, a medical history of migraine, and a suspected family history of stroke, further cranial magnetic resonance imaging scan was performed and revealed severe leukoencephalopathy, prompting further investigation. The diagnosis was revised to CADASIL after Arg587Cys NOTCH3 mutation was confirmed. This case highlights the evolving process of affective disorder diagnosis and underlying organic etiologies. Based on the overlap of white matter hyperintensities, NOTCH3 mutation, and valproate therapy in bipolar disorder and CADASIL, bipolar II depression may be a poorly recognized manifestation of CADASIL. Well-designed clinical trials are warranted to verify the current findings.

Anxiolytic and neuroprotective effects of the Traditional Chinese Medicinal formulation Dan-zhi-xiao-yao-san in a rat model of chronic stress.

Dan-zhi-xiao-yao-san is a Traditional Chinese Medicinal formulation widely used for the treatment of neuropsychological disorders. The present study examined the anxiolytic and neuroprotective effects of Dan-zhi-xiao-yao-san in a rat model of chronic stress. The results of an elevated plus maze test showed that Dan­zhi­xiao­yao­san significantly attenuated the levels of anxiety-induced stress as evidenced by increases in the time spent in the open arm region, as well as the percentage of entries into this area. In addition, Dan-zhi-xiao-yao-san alleviated stress­induced neuronal death, as indicated by histological examination. Furthermore, mechanistic studies suggested that the anxiolytic and neuroprotective effects of Dan-zhi-xiao-yao-san may be mediated via attenuation of chronic stress­induced upregulation of α­synuclein and corticosterone, and downregulation of protein phosphatase 2A (PP2A) in the hippocampal region of the brain at the mRNA and protein level. In addition, Dan­zhi­xiao­yao­san decreased the serum levels of stress­induced corticosterone in the model animals. In conclusion, the present study demonstrated that Dan­zhi­xiao­yao­san exerted anxiolytic and neuroprotective effects in a rat model of chronic stress via attenuation of stress­induced upregulation of α­synuclein and corticosterone, and downregulation of PP2A in the hippocampus.