Genistein attenuates brain damage induced by transient cerebral ischemia through up-regulation of Nrf2 expression in ovariectomized rats

Objective: Postmenopausal women possess higher incidence of stroke and worse prognosis. Although estrogen replacement therapy has obvious neuroprotective effects against stroke, it is always accompanied with several adverse effects and undesired outcomes. Genistein, a natural phytoestrogen, has been indicated to be a potential neuroprotective alternative for postmenopausal women against stroke. However, the role and mechanism of genistein’s neuroprotective effects against stroke in ovariectomized rats have rarely been explored.

Methods: In this study, ovariectomized rats were treated with genistein (10 mg/kg) or vehicle daily for two weeks before they received middle cerebral artery occlusion (MCAO) and reperfusion. After 72 hours of reperfusion, the neurological function was evaluated by Garcia test, infarct volume was detected by 2,3,5-triphenyltetrazolium chloride staining, and neuronal damage was detected by Nissl staining. In addition, ROS production and the expression of Nrf2, NQO1 and cleaved-Caspase3 in the ischemic penumbra were detected.

Results: The results showed that genistein treatment significantly improved the neurological outcome, reduced infarct volume, increased Nrf2 and NQO1 expression, and reduced ROS production and cleaved-Caspase3 expression in ovariectomized rats.

Discussion: Our findings indicated that treatment with genistein could alleviated oxidative stress injury induced by cerebral ischemia in ovariectomized rats via promoting Nrf2 and NQO1 expression, which provide a new molecular mechanism for the neuroprotective effects of genistein against stroke in postmenopausal women.     

Abnormalities in P300 components in depression: an ERP-sLORETA study

Background: Alterations in P300 components occur in depressed patients, but the brain regions contributing to these changes remain unclear.

Aims: Thus, the aim of the present study was to examine the underlying neural activation of P300 components in patients with depression to explore brain regions related to depression.

Methods: P300 components were evoked by an oddball auditory paradigm and recorded from 30 patients with current depression, as well as 30 age-, gender-, and education level-matched healthy controls. The standardized Low-Resolution Brain Electromagnetic Tomography (sLORETA) method was used to explore the source activation of P300 components.

Results: Compared with healthy controls, depressed patients tended to exhibit lower P200 and P300 amplitudes and prolonged P300 latency. In depressed patients, P200 source activations were reduced in the right insula, right precentral gyrus, left anterior cingulate, medial frontal gyrus, superior frontal gyrus, and middle frontal gyrus. Decreased source activations of P300 were identified in the right insula, postcentral gyrus, superior temporal gyrus, inferior parietal lobule, transverse temporal gyrus, cingulate gyrus, precentral gyrus, middle frontal gyrus, superior frontal gyrus, medial frontal gyrus, and paracentral gyrus.

Conclusions: Extensive dysfunction over the right hemisphere and bilateral prefrontal dysfunction may be involved in the pathophysiology of depression.     

Measuring abnormal intrinsic brain activities in patients with retinal detachment using amplitude of low-frequency fluctuation: a resting-state fMRI study

Objective: The targets of this study were to access the alternations of spontaneous brain activity in RD patients by amplitude of low-frequency fluctuation (ALFF) method and to explore their relationships with clinical behavioral performance.

Methods: A total of 20 patients with RD (6 males and 14 females), and 20 healthy controls (HCs) (6 males and 14 females) were recruited, and were matched in sex and age. All participants finished the functional magnetic resonance imaging (fMRI) scanning. We applied the ALFF method to detect the spontaneous brain activity. Receiver operating characteristic (ROC) curve was applied to distinguish RD Patients from HCs.

Results: RD patients showed decreased ALFF values in the right occipital lobe and right medial frontal gyrus and increased ALFF values in the right frontal superior orbital and left inferior temporal gyrus when compared with HCs. In RD patients, we did not find any relationship between the mean ALFF values and the clinical behavioral performances.

Conclusion: The RD patients exhibited abnormal spontaneous brain activity in vision and vision related brain regions, which might explore potential pathological mechanism of acute vision loss in RD patients.     

Executive control deficits correlate with reduced frontal white matter volume in multiple sclerosis

Introduction: Executive control deficits are frequently reported in patients with multiple sclerosis (MS). We have previously proposed that in the context of competing automatic and volitional processes, such deficits may in part reflect poor resolution of response conflict. This study aimed to investigate the neuropathological underpinnings of executive control deficits in MS, focusing on the frontostriatal system proposed to mediate executive control.

Method: Forty-one MS patients and 25 healthy controls completed measures of executive control that have previously been used to characterize deficit in MS: antisaccade and endogenously cued saccade paradigms, and the Stroop color and word test. Relationships between task performance and volumetric measures of frontal white matter, frontal gray matter, striatum, and pallidum were investigated.

Results: MS participants performed significantly more poorly on the Stroop and antisaccade tasks than controls. For MS patients, higher erroneous responding on the antisaccade task was related to reduced frontal white matter volume.

Conclusion: These findings suggest that loss of frontal white matter may underlie executive control deficits in MS, and provides information that may inform the development of targeted cognitive training strategies in MS.     

Aphasia elicited by electrical stimulation of the right anterior corpus callosum

Background: The preoperative evaluation of drug-resistant focal epilepsy patients considered for epilepsy surgery provides a unique setting to evaluate cortical function and corresponding networks.

Aims: Whereas there is a wealth of data on cortical language localization using electrical stimulation with subdural electrodes, there is much less experience with stimulation of depth electrodes in the white matter and an effect on language function via electric stimulation of the corpus callosum has not been demonstrated so far.

Methods & Procedures: We report on a 29-year-old epilepsy patient with bilateral language representation who underwent pre-surgical EEG-video-monitoring for drug-resistant, non-lesional right frontal lobe epilepsy.

Outcomes & Results: Electric stimulation of a stereotactically implanted depth electrode in the right anterior corpus callosum elicited paraphasia and anomia. The precise mechanism could be an inhibition of cortical language areas in the left hemisphere, the right hemisphere or interference with transcallosal connectivity.

Conclusions: This is the first report on language dysfunction through electric stimulation in the corpus callosum, most likely through an inhibition of cortical language areas in the left frontal lobe.     

Episodic ataxia type 2 characterised by recurrent dizziness/vertigo: a report of four cases

Purpose: To report the clinical features and gene mutations in four episodic ataxia type 2 (EA2) patients whose main presentation was recurrent dizziness/vertigo.

Methods: Clinical data of four EA2 patients (three familial EA2 cases and one sporadic case) with recurrent dizziness/vertigo were collected to assess nystagmus and eye movement. Gene mutations were identified by whole exome sequencing.

Results: The three patients in family 1 experienced disease onset before 8 years of age, presented with a chief complaint of episodic dizziness, muscle weakness of the lower limbs and the inability to walk. These symptoms lasted a few hours and then subsided. The proband also had gaze-evoked nystagmus during attacks. Videonystagmography demonstrated that the saccade velocity was low, smooth pursuit was type III, and gain was abnormal at 0.1, 0.2 and 0.4?Hz. An optokinetic nystagmus test showed that the left eye optokinetic nystagmus disappeared, and the right eye optokinetic nystagmus weakened. A head-shaking test produced a left horizontal nystagmus. Gene analysis identified a novel c.1558?+?2T?>?G splice site mutation in the CACNA1A gene in the proband and his mother. The fourth patient was sporadic, with an onset age of 3 years. He mainly suffered from episodic vertigo, accompanied by severe anxiety and depression. He carried a CACNA1A mutation, c.4636C?>?T, which is a previously reported pathogenic mutation.

Conclusions: The onset of symptoms in these EA2 patients was early. The patients mainly presented recurrent dizziness/vertigo, with the absence of characteristic episodic ataxia. Detection of CACNA1A mutations facilitates the diagnosis of EA2.     

A how-to guide to aphasia services: celebrating Professor Linda Worrall’s contribution to the field

Background: This article recognises Professor Linda Worrall’s contribution to aphasiology and discusses research themes which have grown from her work.

Aims: To review, summarise, and discuss literature relating to four themes which have emerged from the work of Professor Worrall: (1) Research capacity building; (2) Implementation of research evidence in clinical practice; (3) Meaningful outcome measurement; and (4) Improvement of psychological and emotional outcomes.

Main contribution: A review of the literature, with examples of practical applications.

Conclusions: The work of Professor Worrall has greatly influenced the field of aphasia; her legacy is the research capacity she has built in Australia and around the world.     

Analysis of Lithuanian CYP2D6 polymorphism and its relevance to psychiatric care of the local population

Background: CYP450 system gene CYP2D6 polymorphisms have been associated with an altered response to psychotropic drugs. While there exists interindividual and interethnic differences of clinical significance, there is no data concerning the Lithuanian population.

Aims: To determine the distribution of CYP2D6 alleles and predicted phenotype in the Lithuanian population, compare it to other Europeans and find the differences between patients with affective disorders and the healthy population.

Methods: Our study sample consisted of 179 subjects that included 104 healthy volunteers and 75 patients with clinical diagnosis of affective disorders according to ICD-10AM classification, treated in hospital settings. DNA samples were taken from the blood and alleles of the CYP2D6 gene were determined for each participant. Frequencies were compared to other Europeans.

Results: The frequency of the most common alleles *1 and *2 was 45.0% and 28.8% accordingly. Dysfunctional *5 (1 vs. 30, p?<?.002) allele was less frequent in Lithuania inhabitants than previously established in other Europeans. There were no polymorphisms of the CYP2D6 gene that could be associated with changes in drug metabolism in the patients. The functional CYP2D6 *2 allele was more prevalent in the control group, while the non functional CYP2D6 *4 allele was more prevalent in the patient group (p?<?.05 for both cases).

Conclusion: The genetic makeup of Lithuanians was generally comparable to other Europeans, but fewer Lithuanians had non-functional *5 allele. More patients had non-functional alleles. Study findings contradict previous results from other countries, where CYP2D6 gene polymorphism was associated with treatment outcomes.     

Voluntary exercise improves cognitive deficits in female dominant-negative DISC1 transgenic mouse model of neuropsychiatric disorders

Objectives: Physical exercise has gained increasing interest as a treatment modality that improves prognosis in psychiatric patients. The disrupted in schizophrenia 1 (DISC1) gene is a candidate gene for major mental illness. In this study, we aimed to determine whether voluntary wheel running can improve cognitive deficits of dominant-negative DISC1 transgenic mice (DN-DISC1).

Methods: DN-DISC1 and control mice (10-week-old male and female) were placed for 14 days in a cage with or without access to a running wheel. Two weeks later, mice underwent behavioural tests evaluating cognition and social approach and recognition.

Results: Voluntary exercise improved performance in the novel object recognition test, restored the impairment in spatial memory in the Y maze, and reversed the deficit in social recognition memory in DN-DISC1 females. DN-DISC1 males did not exhibit behavioural deficits at baseline. Tissue analysis revealed that exercise induced a significant increase in hippocampal expression of doublecortin (DCX), brain-derived neurotrophic factor (BDNF) and cannabinoid receptor type 1 (CB1R) only in DN-DISC1 females.

Conclusions: Voluntary exercise is beneficial in attenuating cognitive deficits observed in a rodent model relevant for neuropsychiatric disorders. The data add a preclinical aspect to the accumulating clinical data supporting the incorporation of physical exercise to patients’ care.     

Effect of activity-based mirror therapy on lower limb motor-recovery and gait in stroke: A randomised controlled trial

Objective: To determine the effect of activity-based mirror therapy (MT) on motor recovery and gait in chronic poststroke hemiparetic subjects.

Design: A randomised, controlled, assessor-blinded trial.

Setting: Rehabilitation institute.

Participants: Thirty-six chronic poststroke (15.89?±?9.01 months) hemiparetic subjects (age: 46.44?±?7.89 years, 30 men and functional ambulation classification of median level 3).

Interventions: Activity-based MT comprised movements such as ball-rolling, rocker-board, and pedalling. The activities were provided on the less-affected side in front of the mirror while hiding the affected limb. The movement of the less-affected lower limb was projected as over the affected limb. Conventional motor therapy based on neurophysiological approaches was also provided to the experimental group. The control group received only conventional management.

Main outcome measures: Brunnstrom recovery stages (BRS), Fugl-Meyer assessment lower extremity (FMA-LE), Rivermead visual gait assessment (RVGA), and 10-metre walk test (10-MWT).

Results: Postintervention, the experimental group exhibited significant and favourable changes for FMA-LE (mean difference?=?3.29, 95% CI?=?1.23–5.35, p?=?.003) and RVGA (mean difference?=?5.41, 95% CI?=?1.12–9.71, p?=?.015) in comparison to the control group. No considerable changes were observed on 10-MWT.

Conclusions: Activity-based MT facilitates motor recovery of the lower limb as well as reduces gait deviations among chronic poststroke hemiparetic subjects.     

Depression in type 1 diabetes and risk of dementia

Objective: Depression afflicts 14% of individuals with type 1 diabetes (T1D). Depression is a robust risk factor for dementia but it is unknown if this holds true for individuals with T1D, who recently started living to an age conferring dementia risk. We examined if depression is a dementia risk factor among elderly individuals with T1D.

Methods: 3,742 individuals with T1D age ≥50 were followed for dementia from 1/1/96-9/30/2015. Depression, dementia, and comorbidities were abstracted from electronic medical records. Cox proportional hazard models estimated the association between depression and dementia adjusting for demographics, glycosylated hemoglobin, severe dysglycemic epidsodes, stroke, heart disease, nephropathy, and end stage renal disease. The cumulative incidence of dementia by depression was estimated conditional on survival dementia-free to age 55.

Results: Five percent (N = 182) were diagnosed with dementia and 20% had baseline depression. Depression was associated with a 72% increase in dementia (fully adjusted HR = 1.72; 95% CI:1.12-2.65). The 25-year cumulative incidence of dementia was more than double for those with versus without depression (27% vs. 12%).

Conclusions: For people with T1D, depression significantly increases dementia risk. Given the pervasiveness of depression in T1D, this has major implications for successful aging in this population recently living to old age.     

Rapamycin inhibits activation of AMPK-mTOR signaling pathway-induced Alzheimer’s disease lesion in hippocampus of rats with type 2 diabetes mellitus

Background: Type 2 diabetes mellitus (T2DM) is strongly correlated with Alzheimer’s disease (AD). Rapamycin has important uses in oncology, cardiology and transplantation medicine. This study aims to investigate effects of rapamycin on AD in hippocampus of T2DM rat by AMPK/mTOR signaling pathway.

Methods: Morris water maze test was applied to evaluate the learning and memory abilities. The fasting plasma glucose (FBG), glycosylated haemoglobin, total cholesterol, triglyceride and serum insulin level were measured. RT-qPCR and Western blot analysis were performed to test expression of AMPK and mTOR. Immunohistochemistry was used to detect the Aβ deposition and immunoblotting to test the total tau, p-tau and Aβ precursor APP expressions.

Results: After treated with rapamycin, T2DM rats and rats with T2DM and AD showed increased learning-memory ability, and decreased levels of FBG, glycosylated hemoglobin, total cholesterol, triglyceride and serum insulin, decreased expression of APP and p-tau, increased AMPK mRNA expression and p-AMPK and decreased Aβ deposition, mTOR mRNA expression and p-mTOR.

Conclusion: The study demonstrated that rapamycin reduces the risk of AD in T2DM rats and inhibits activation of AMPK-mTOR signaling pathway, thereby improving AD lesion in hippocampus of T2DM rats.     

French translation and validation of a fragile X syndrome screening checklist

Background: Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability among men. This syndrome is frequently underdiagnosed in adults. The aim of this study was to develop and validate a French translation of the screening checklist Fragiele-X screeningslijst.

Method: The validation sample for the translated checklist included 22 pairs of men between the ages of 18 and 52, matched by age and degree of intellectual impairment.

Results: The translated checklist achieved coefficients of 0.92 for internal consistency, 0.90 for test-retest reliability and 0.65 for inter-rater reliability. These psychometric properties are commensurate with those of the original checklist.

Conclusion: Therefore, the translated checklist developed in this study can be considered a valid screening instrument for the detection of FXS in men with intellectual disabilities.

Abbreviations: FXS: fragile X syndrome; FMR1: fragile X mental retardation 1 (gene)     

Utility of the Taiwan version of the Screening Tool for Autism in Two-Year-Olds to detect autism in children aged three years

Background: The Taiwan version of the Screening Tool for Autism in Two-Year-Olds (T-STAT) had been developed for identifying autism disorder (AD) in children aged 24–35 months. Two studies were performed to elucidate its utility for AD in children aged 36–48 months.

Method: In Study 1, the receiver operating characteristics were utilised to select a cutoff score for the T-STAT with 34 children with AD and with developmental delay (DD). In study 2, 147 children with AD, DD, and pervasive developmental disorder-not otherwise specified (PDD-NOS) were participated for validation.

Results: In study 1, the results indicated that a cutoff of 1.25 would yield high sensitivity and specificity. In study 2, the concurrent agreements between T-STAT risk and clinical diagnosis were high for children with AD and DD, but not PDD-NOS.

Conclusions: The results showed that T-STAT was a promising Level 2 screening tool for AD in children aged three years.     

Habilitation of very preterm infants at a Post Acute Care Inpatient Rehabilitation (PACIR) center after neonatal intensive care unit (NICU) discharge

Objective: To investigate whether Post-Acute Care Inpatient Rehabilitation (PACIR) admission after NICU stay affects the total length of stay (LOS) of very preterm (VPT: ≤30 weeks of gestation) infants.

Methods: A retrospective case control study of VPT infants d/c’d from the NICU at Maria Fareri Children’s Hospital (MFCH) to either a PACIR (Blythedale Children’s Hospital: BH) for convalescent care (cases) or directly home (controls).

Results: 35 cases and 70 controls. Total LOS (MFCH + BH) was longer for cases [196 vs. 97 days]. At the time of d/c from MFCH, Special Health Care Needs (SHCN) amongst cases were greater than controls, however, became similar at the time of home d/c. The majority of cases achieved habilitation goals at the PACIR.

Conclusions: Although LOS was longer for patients transferred to a PACIR, habilitation at BH Hospital reduced the SHCN at the time of home d/c amongst cases.     

Role of hesperidin in P2X3 receptor-mediated neuropathic pain in the dorsal root ganglia

Aim: This study investigated whether the neuronal P2X3 receptor in rat dorsal root ganglia (DRG) mediated the effects of hesperidin on neuropathic pain.

Materials and methods: The chronic constriction injury (CCI) model was used as a model of neuropathic pain. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured. The mRNA and protein expression levels were assayed by real-time RT-PCR and Western blotting.

Results: The results showed that mechanical and thermal hyperalgesia in the CCI rats were increased as compared to those in the sham group. The expression levels of P2X3 mRNA and protein in CCI rats were higher than those in the sham group. Dual-labelling immunofluorescence showed that the elevated P2X3 receptor was co-expressed with the neuronal marker NeuN in the DRG of CCI rats. Hesperidin treatment decreased both the mechanical and thermal hyperalgesia, and upregulated P2X3 expression in the CCI rats. Hesperidin treatment also reduced the ERK1/2 phosphorylation in the DRG of CCI rats. Moreover, hesperidin inhibited the P2X3 agonist ATP-induced currents in HEK293 cells transfected with the P2X3 plasmid. Therefore, hesperidin treatment could reverse the elevated expression of neuronal P2X3 receptor and reduce the activation of ERK1/2 in the DRG of CCI rats.

Conclusions: Our findings suggested that hesperidin inhibited the nociceptive transmission mediated by the P2X3 receptor in neurons of DRG, and thus, relieved the mechanical and thermal hyperalgesia in CCI rats.     

A 9-year neuropsychological report of a patient with LGI1-associated limbic encephalitis

Introduction: Anti-leucine-rich glioma-inactivated 1 limbic encephalitis (LGI1-LE) is an autoimmune disorder associated with antibodies to voltage-gated potassium channels (VGKC). It is a non-paraneoplastic and partially reversible encephalitis that can be diagnosed via serological testing. Untreated LGI1-LE can be associated with neurocognitive as well as neuropsychiatric sequelae. Here we report the neuropsychological and clinical profile of a patient with LGI1-LE following three different treatment approaches: plasmapheresis (PA), intravenous immunoglobulin (IVIG), and corticosteroids (CO).

Method: We investigated our patient with 10 neuropsychological evaluations obtained over a 9-year follow-up period. Multiple MRI scans, EEG recordings, neurological examinations, and serum tests were also obtained.

Results: The neurocognitive profile of our patient was characterized by long-term memory impairment (verbal and visual-spatial), and deficits in aspects of executive functioning and language. Neuropsychiatric symptoms of depression and anxiety were noted intermittently.

Conclusions: Non-specific treatment prior to diagnosis had marginal effects on neurocognitive profile, neuropsychiatric symptoms, or control of epileptic seizure. In contrast, specific treatments for LGI1-LE following diagnosis resulted in neurocognitive improvement and epileptic control. Among the three treatments, IVIG and CO had the most beneficial impact on neurocognitive status, likely due to the continuity of administration.     

Schisanhenol improves learning and memory in scopolamine-treated mice by reducing acetylcholinesterase activity and attenuating oxidative damage through SIRT1-PGC-1α-Tau signaling pathway

Purpose: Schisanhenol is a compound derived from the fruit of a traditional Chinese herb Schisandra rubriflora. The aim of the present study was to evaluate the effect of Schisanhenol on the cognitive impairment induced by scopolamine.

Material and Methods: Male mice were randomly divided into three Schisanhenol groups (10, 30, 100 mg/kg), Galantamine group (3 mg/kg), model group (1mg/kg scopolamine), and vehicle control group (normal saline). The learning and memory ability of mice was monitored by water morris maze. Hippocampus of mice were collected after behavioral testing and the activity of SOD, MDA, GSH-px, AChE were measured with standard biochemical procedures. Western blotting was used to analyze the expression of SIRT1, PGC-1α, phosphorylated Tau proteins.

Results: Intraperitoneal administration of Schisanhenol (10, 30 or 100 mg/kg) significantly attenuated scopolamine-induced cognitive impairment in water morris maze. In addition, Schisanhenol increased the activity of SOD and GSH-px while decreased the content of AChE and MDA. Furthermore, western blotting analysis revealed that Schisanhenol increased the levels of SIRT1 and PGC-1α and decreased the level of phosphorylated Tau protein (Ser 396) significantly in the hippocampal tissues.

Conclusions: Our findings indicated that Schisanhenol can attenuate scopolamine-induced learning impairment and enhance cognitive function, the mechanism via improve the cholinergic system and antioxidant ability, activate SIRT1-PGC1α signaling, inhibit the phosphorylation of Tau, and would be an effective candidate against cognitive disorders, such as Alzheimer's disease.