Proton spectroscopy in Alzheimer`s disease and cognitive impairment no dementia: A community-based study

Objective: To describe the findings of proton magnetic resonance spectroscopy (H-1-MRS) in Alzheimer`s disease (AD) and cognitive impairment, no dementia (CIND) elderly from a community-based sample. Methods: Thirteen patients with AD, 12 with CIND and 15 normal individuals were evaluated. The H-1-MRS was performed in the right temporal, left parietal and medial occipital regions studying the metabolites N-acetylaspartate (NAA), creatine (Cr), choline (Cho) and myoinositol (ml). The clinical diagnosis was based on standardized cognitive tests - MMSE and CAMDEX - and the results correlated with the H-1-MRS. Results: Parietal Cho was higher in control individuals and lower in CIND subjects. AD and control groups were better identified by temporal and parietal ml combined with the temporal NAA/Cr ratio. CIND was better identified by parietal Cho. Conclusion: The H-1-MRS findings confirmed the hypothesis that metabolic alterations are present since the first symptoms of cognitively impaired elderly subjects. These results suggest that combining MRS from different cerebral regions can help in the diagnosis and follow-up of community elderly individuals with memory complaints and AD. Copyright (C) 2008 S. Karger AG, Basel.

Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial

Background Two recent clinical studies support the feasibility of trials to evaluate the disease-modifying properties of lithium in Alzheimer`s disease, although no benefits were obtained from short-term treatment. Aims To evaluate the effect of long-term lithium treatment on cognitive and biological outcomes in people with amnestic mild cognitive impairment (aMCI). Method Forty-five participants with aMCI were randomised to receive lithium (0.25-0.5mmol/l) (n=24) or placebo (n = 21) in a 12-month, double-blind trial. Primary outcome measures were the modification of cognitive and functional test scores, and concentrations of cerebrospinal fluid (CSF) biomarkers (amyloid-beta peptide (A beta(42)), total tau (T-tau), phosphorylated-tau) (P-tau). Trial registration: NCT01055392. Results Lithium treatment was associated with a significant decrease in CSF concentrations of P-tau (P=0.03) and better perform-ance on the cognitive subscale of the Alzheimer`s Disease Assessment Scale and in attention tasks. Overall tolerability of lithium was good and the adherence rate was 91%. Conclusions The present data support the notion that lithium has disease-modifying properties with potential clinical implications in the prevention of Alzheimer`s disease.

Treatment with cannabidiol reverses oxidative stress parameters, cognitive impairment and mortality in rats submitted to sepsis by cecal ligation and puncture

Oxidative stress plays an important role in the development of cognitive impairment in sepsis. Here we assess the effects of acute and extended administration of cannabidiol (CBD) on oxidative stress parameters in peripheral organs and in the brain, cognitive impairment, and mortality in rats submitted to sepsis by cecal ligation and perforation (CLP). To this aim, male Wistar rats underwent either sham operation or CLP. Rats subjected to CLP were treated by intraperitoneal injection with ""basic support"" and CBD (at 2.5, 5, or 10 mg/kg once or daily for 9 days after CLP) or vehicle. Six hours after CLP (early times), the rats were killed and samples from lung, liver, kidney, heart, spleen, and brain (hippocampus, striatum, and cortex) were obtained and assayed for thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. On the 10th day (late times), the rats were submitted to the inhibitory avoidance task. After the test, the animals were killed and samples from lung, liver, kidney, heart, spleen, and brain (hippocampus) were obtained and assayed for TBARS formation and protein carbonyls. The acute and extended administration of CBD at different doses reduced TBARS and carbonyl levels in some organs and had no effects in others, ameliorated cognitive impairment, and significantly reduced mortality in rats submitted to CLP. Our data provide the first experimental demonstration that CBD reduces the consequences of sepsis induced by CLP in rats, by decreasing oxidative stress in peripheral organs and in the brain, improving impaired cognitive function, and decreasing mortality. (C) 2010 Elsevier B.V. All rights reserved.

Multi-system neurological disease is common in patients with OPA1 mutations

Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal `dominant optic atrophy plus` variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.

Conductive hearing loss in children with bronchopulmonary dysplasia: A longitudinal follow-up study in children aged between 6 and 24 months

Aims: To determine the occurrence of isolated and recurrent episodes of conductive hearing loss (CHL) during the first two years of life in very low birth weight (VLBW) infants with and without bronchopulmonary dysplasia (BPD). Study design, subjects and outcome measures: In a longitudinal clinical study. 187 children were evaluated at 6, 9, 12,15 18 and 24 months of age by visual reinforcement audiometry, tympanometry and auditory brain response system. Results: Of the children with BPD, 54.5% presented with episodes of CHL, as opposed to 34.7% of the children without BPD. This difference was found to be statistically significant. The recurrent or persistent episodes were more frequent among children with BPD (25.7%) than among those without BPD (8.3%). The independent variables that contributed to this finding were small for gestational age and a 5 min Apgar score. Conclusions: Recurrent CHL episodes are more frequent among VLBW infants with BPD than among VLBW infants without BPD. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Assessment of two central auditory tests in elderly patients without hearing complaints

Speech understanding disorders in the elderly may be due to peripheral or central auditory dysfunctions. Asymmetry of results in dichotic testing increases with age, and may reflect on a lack of inter-hemisphere transmission and cognitive decline. Aim: To investigate auditory processing of aged people with no hearing complaints. Study design: clinical prospective. Materials and Methods: Twenty-two voluntary individuals, aged between 55 and 75 years, were evaluated. They reported no hearing complaints and had maximal auditory thresholds of 40 dB HL until 4 KHz, 80% of minimal speech recognition scores and peripheral symmetry between the ears. We used two kinds of tests: speech in noise and dichotic alternated dissyllables (SSW). Results were compared between males and females, right and left ears and between age groups. Results: There were no significant differences between genders, in both tests. Their Left ears showed worse results, in the competitive condition of SSW. Individuals aged 65 or older had poorer performances than those aged 55 to 64. Conclusion: Central auditory tests showed worse performance with aging. The employment of a dichotic test in the auditory evaluation setting in the elderly may help in the early identification of degenerative processes, which are common among these patients.

Unilateral hearing loss: benefits and satisfaction from the use of hearing aids

A unilateral hearing loss is characterized by reduced hearing in one ear. The problems caused by sensory deprivation can be minimized with the use of hearing aids (HA). Aim: To analyze the correlation between the prescribed grain and the insertion gain difference and with the results obtained regarding the benefit and satisfaction with the use of hearing aids in unilateral hearing impaired patients. Materials and Methods: Prospective study with 15 subjects, mean age of 41.6 years, of both genders, users of hearing aids effectively. We used the International Questionnaire Results for hearing aids (International Outcome Inventory for Hearing Aids - IOI-HA), measured with a probe microphone. Results: The mean values in the analyses of the IOI-HA per item were positive and higher than four points. In relation to the objective measures, the frequencies in which we obtained the gain values which were closer to the target were: 1K Hz, 2K Hz and 500 Hz, respectively. Conclusion: The satisfaction of individuals using hearing aid unilaterally is not completely correlated to the prescribed gain, because even if the target is not being reached in some frequencies, the individuals were pleased as to the use of their hearing aids.

Saethre-Chotzen Syndrome, Pro136His TWIST Mutation, Hearing Loss, and External and Middle Ear Structural Anomalies: Report on a Brazilian Family

Objective: To describe the clinical, speech, hearing, and imaging findings in three members of a Brazilian family with Saethre-Chotzen syndrome (SCS) who presented some unusual characteristics within the spectrum of the syndrome. Design: Clinical evaluation was performed by a multidisciplinary team. Direct sequencing of the polymerase chain reaction amplified coding region of the TWIST1 gene, routine and electrophysiological hearing evaluation, speech evaluation, and imaging studies through computed tomography (CT) scan and magnetic resonance imaging (MRI) were performed. Results: TWIST1 gene analysis revealed a Pro136His mutation in all patients. Hearing evaluation showed peripherial and mixed hearing loss in two of the patients, one of them with severe unilateral microtia. Computed tomography scan showed structural middle ear anomalies, and MRI showed distortion of the skull contour as well as some of the brain structures. Conclusions: We report a previously undescribed TWIST1 gene mutation in patients with SCS. There is evidence that indicates hearing loss (conductive and mixed) can be related both with middle ear (microtia, high jugular bulb, and enlarged vestibules) as well as with brain stem anomalies. Here we discuss the relationship between the gene mutation and the clinical, imaging, speech, and hearing findings.

Telehealth in audiology: The need and potential to reach underserved communities

Permanent hearing loss is a leading global health care burden, with 1 in 10 people affected to a mild or greater degree. A shortage of trained healthcare professionals and associated infrastructure and resource limitations mean that hearing health services are unavailable to the majority of the world population. Utilizing information and communication technology in hearing health care, or tele-audiology, combined with automation offer unique opportunities for improved clinical care, widespread access to services, and more cost-effective and sustainable hearing health care. Tele-audiology demonstrates significant potential in areas such as education and training of hearing health care professionals, paraprofessionals, parents, and adults with hearing disorders; screening for auditory disorders; diagnosis of hearing loss; and intervention services. Global connectivity is rapidly growing with increasingly widespread distribution into underserved communities where audiological services may be facilitated through telehealth models. Although many questions related to aspects such as quality control, licensure, jurisdictional responsibility, certification and reimbursement still need to be addressed; no alternative strategy can currently offer the same potential reach for impacting the global burden of hearing loss in the near and foreseeable future.

Remote probe microphone measurement to verify hearing aid performance

We assessed the feasibility of obtaining probe microphone measurements of hearing aids at a distance. Face-to-face and remote probe microphone measurements were carried out in 60 hearing aid users (mean age 67 yrs) with uni- or bilateral hearing losses (105 ears tested). The participant and a facilitator were located in a room equipped with a probe microphone system interfaced to a PC. Desktop videoconferencing and application sharing was used to allow an audiologist in another room to instruct the facilitator and control the equipment via the LAN. There were significant correlations between face-to-face and remote real ear unaided response (REUR), aided response (REAR) and insertion gain (REIG) at seven discrete frequencies from 250 to 6000 Hz. Differences between face-to-face and remote responses were within the reported variability for probe microphone measurements themselves. The results show that remote probe microphone measurements are feasible and might improve the quality of public hearing aid services and professional training in Brazil.

Persistent Impairment of Testicular Histology and Sperm Motility in Adult Rats Treated with Cisplatin at Peri-Puberty

Cisplatin is one of the most widely used and effective chemotherapeutic agents for the treatment of several human malignancies. This study evaluated the effects of peri-pubertal cisplatin administration on several reproductive end-points and the reversibility of these effects in adulthood. Peri-pubertal Wistar male rats (45 days old) were divided into two groups: control (saline 0.9%) and cisplatin (1 mg/kg/day, 5 days/week, for 3 weeks, i.p.). The study was conducted in two steps and evaluations were performed at ages of 66 (post-pubertal age) and 140 (adult age) days on: (i) organ weights, serum gonadotropins and testosterone levels, sperm counts, motility and morphology, testicular histomorphometry, spermatogenesis kinetics, Sertoli cell number and in situ detection of apoptotic germ cells and (ii) sexual behaviour, fertility and intratesticular testosterone. At the end of cisplatin therapy, rats showed reductions in sperm production and reserves, sperm with progressive movement, tubular diameter, intratesticular testosterone and fertility potential, but increased numbers of TUNEL-positive seminiferous tubules, immotile sperm and pre-implantation losses compared with control. Moreover, cisplatin-treated post-pubertal rats displayed impaired testicular histopathology and sexual behaviour. Serum gonadotropins and testosterone levels, sperm morphology, spermatogenesis kinetics and Sertoli cell number were comparable between experimental groups at both ages. Alterations found in post-puberty were recovered at adulthood, except for sperm motility and damage to testicular histology. The persistence of these cisplatin effects, despite the unaltered fertility after natural mating in rats, may have implications for reproductive function of young boys undergoing cancer therapy, given the lower reproductive efficiency in human beings compared with rats.

Autonomic impairment after myocardial infarction: Role in cardiac remodelling and mortality

P>1. Impairmant of baroreflex sensitivity (BRS) has been implicated in the reduction of heart rate variability (HRV) and in the increased risk of death after myocardial infarction (MI). In the present study, we investigated whether the additional impairment in BRS induced by sinoaortic baroreceptor denervation (SAD) in MI rats is associated with changes in the low-frequency (LF) component of HRV and increased mortality rate. 2. Rats were randomly divided into four groups: control, MI, denervated (SAD) and SAD + MI rats. Left ventricular (LV) function was evaluated by echocardiography. Autonomic components were assessed by power spectral analysis and BRS. 3. Myocardial infarction (90 days) reduced ejection fraction (by similar to 42%) in both the MI and SAD + MI groups; however, an increase in LV mass and diastolic dysfunction were observed only in the SAD + MI group. Furthermore, BRS, HRV and the LF power of HRV were reduced after MI, with an exacerbated reduction seen in SAD + MI rats. The LF component of blood pressure variability (BPV) was increased in the MI, SAD and SAD + MI groups compared with the control group. Mortality was higher in the MI groups compared with the non-infarcted groups, with an additional increase in mortality in the SAD + MI group compared with the MI group. Correlations were obtained between BRS and the LF component of HRV and between LV mass and the LF component of BPV. 4. Together, the results indicate that the abolishment of BRS induced by SAD in MI rats further reduces the LF band of HRV, resulting in a worse cardiac remodelling and increased mortality in these rats. These data highlight the importance of this mechanism in the prognosis of patients after an ischaemic event.

Potential Role of Growth Hormone in Impairment of Insulin Signaling in Skeletal Muscle, Adipose Tissue, and Liver of Rats Chronically Treated with Arginine

We have shown that rats chronically treated with Arginine (Arg), although normoglycemic, exhibit hyperinsulinemia and decreased blood glucose disappearance rate after an insulin challenge. Attempting to investigate the processes underlying these alterations, male Wistar rats were treated with Arg (35 mg/d), in drinking water, for 4 wk. Rats were then acutely stimulated with insulin, and the soleus and extensorum digitalis longus muscles, white adipose tissue (WAT), and liver were excised for total and/or phosphorylated insulin receptor (IR), IR substrate 1/2, Akt, Janus kinase 2, signal transducer and activator of transcription (STAT) 1/3/5, and p85 alpha/55 alpha determination. Muscles and WAT were also used for plasma membrane (PM) and microsome evaluation of glucose transporter (GLUT) 4 content. Pituitary GH mRNA, GH, and liver IGF-I mRNA expression were estimated. It was shown that Arg treatment: 1) did not affect phosphotyrosine-IR, whereas it decreased phosphotyrosine-IR substrate 1/2 and phosphoserine-Akt content in all tissues studied, indicating that insulin signaling is impaired at post-receptor level; 2) decreased PM GLUT4 content in both muscles and WAT; 3) increased the pituitary GH mRNA, GH, and liver IGF-I mRNA expression, the levels of phosphotyrosine-STAT5 in both muscles, phosphotyrosine-Janus kinase 2 in extensorum digitalis longus, phosphotyrosine-STAT3 in liver, and WAT as well as total p85 alpha in soleus, indicating that GH signaling is enhanced in these tissues; and 4) increased p55 alpha total content in muscles, WAT, and liver. The present findings provide the molecular mechanisms by which insulin resistance and, by extension, reduced GLUT4 content in PM of muscles and WAT take place after chronic administration of Arg, and further suggest a putative role for GH in its genesis, considering its diabetogenic effect. (Endocrinology 150: 2080-2086, 2009)

Peripheral Oxidative Stress Biomarkers in Mild Cognitive Impairment and Alzheimer`s Disease

Oxidative stress has been associated with normal aging and Alzheimer`s disease (AD). However, little is known about oxidative stress in mild cognitive impairment (MCI) patients who present a high risk for developing AD. The aim of this study was to investigate plasma production of the lipid peroxidation marker, malonaldehyde (MDA) and to determine, in erythrocytes, the enzymatic antioxidant activity of catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST) in 33 individuals with MCI, 29 with mild probable AD and 26 healthy aged subjects. GR/GPx activity ratio was calculated to better assess antioxidant defenses. The relationship between oxidative stress and cognitive performance was also evaluated by the Mini Mental State Examination (MMSE). AD patients showed higher MDA levels than both MCI and healthy elderly subjects. MCI subjects also exhibited higher MDA levels compared to controls. Catalase and GPx activity were similar in MCI and healthy individuals but higher in AD. GR activity was lower in MCI and AD patients than in healthy aged subjects. Additionally, GR/GPx ratio was higher in healthy aged subjects, intermediate in MCI and lower in AD patients. No differences in GST activity were detected among the groups. MMSE was negatively associated with MDA levels (r = -0.31, p = 0.028) and positively correlated with GR/GPx ratio in AD patients (r = 0.68, p < 0.001). MDA levels were also negatively correlated to GR/GPx ratio (r = -0.31, p = 0.029) in the AD group. These results suggest that high lipid peroxidation and decreased antioxidant defenses may be present early in cognitive disorders.