White Matter Hyperintensities and the Course of Depressive Symptoms in Elderly People with Mild Dementia

Objectives: To explore the relationship between white matter hyperintensities (WMH) and the prevalence and course of depressive symptoms in mild Alzheimer’s disease (AD) and Lewy body dementia. Design: This is a prospective cohort study conducted in secondary care outpatient clinics in western Norway. Subjects: The study population consisted of 77 elderly people with mild dementia diagnosed according to standardised criteria. Methods: Structured clinical interviews and physical, neurological, psychiatric, and neuropsychological examinations were performed and routine blood tests were taken. Depression was assessed using the depression subitem of the Neuropsychiatric Inventory and the Montgomery-Åsberg Depression Rating Scale (MADRS). A standardised protocol for magnetic resonance imaging scan was used, and the volumes of WMH were quantified using an automated method, followed by manual editing. Results: The volumes of total and frontal deep WMH were significantly and positively correlated with baseline severity of depressive symptoms, and depressed patients had significantly higher volumes of total and frontal deep WMH than non-depressed patients. Higher volumes of WMH were also associated with having a high MADRS score and incident and persistent depression at follow-up. After adjustment for potential confounders, frontal deep WMH, in addition to prior depression and non-AD dementia, were still significantly associated with baseline depressive symptoms (p = 0.015, OR 3.703, 95% CI 1.294–10.593). Similar results emerged for total WMH. Conclusion: In elderly people with mild dementia, volumes of WMH, in particular frontal deep WMH, were positively correlated with baseline severity of depressive symptoms, and seemed to be associated with persistent and incident depression at follow-up. Further studies of the mechanisms that determine the course of depression in mild dementia are needed

Enhancement of cranial nerves in Lyme neuroborreliosis: incidence and correlation with clinical symptoms and prognosis

Purpose Symptoms of cranial neuritis are a common presentation of Lyme neuroborreliosis (LNB). Imaging studies are scarce and report contradictory low prevalence of enhancement compared to clinical studies of cranial neuropathy. We hypothesized that MRI enhancement of cranial nerves in LNB is underreported, and aimed to assess the prevalence and clinical impact of cranial nerve enhancement in early LNB. Methods In this prospective, longitudinal cohort study, 69 patients with acute LNB were examined with MRI of the brain. Enhancement of cranial nerves III–XII was rated. MRI enhancement was correlated to clinical fndings of neuropathy in the acute phase and after 6 months. Results Thirty-nine of 69 patients (57%) had pathological cranial nerve enhancement. Facial and oculomotor nerves were most frequently afected. There was a strong correlation between enhancement in the distal internal auditory canal and parotid segments of the facial nerve and degree of facial palsy (gamma=0.95, p<.01, and gamma=0.93, p<.01), despite that 19/37 nerves with mild-moderate enhancement in the distal internal auditory canal segment showed no clinically evident palsy. Oculomotor and abducens nerve enhancement did not correlate with eye movement palsy (gamma=1.00 and 0.97, p=.31 for both). Sixteen of 17 patients with oculomotor and/or abducens nerve enhancement had no evident eye movement palsy. Conclusions MRI cranial nerve enhancement is common in LNB patients, but it can be clinically occult. Facial and oculomotor nerves are most often afected. Enhancement of the facial nerve distal internal auditory canal and parotid segments correlate with degree of facial palsy.publishedVersio

Cross-Sectional and Longitudinal MRI Brain Scans Reveal Accelerated Brain Aging in Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system. By combining longitudinal MRI-based brain morphometry and brain age estimation using machine learning, we tested the hypothesis that MS patients have higher brain age relative to chronological age than healthy controls (HC) and that longitudinal rate of brain aging in MS patients is associated with clinical course and severity. Seventy-six MS patients [71% females, mean age 34.8 years (range 21–49) at inclusion] were examined with brain MRI at three time points with a mean total follow up period of 4.4 years (±0.4 years). We used additional cross-sectional MRI data from 235 HC for case-control comparison. We applied a machine learning model trained on an independent set of 3,208 HC to estimate individual brain age and to calculate the difference between estimated and chronological age, termed brain age gap (BAG). We also assessed the longitudinal change rate in BAG in individuals with MS. MS patients showed significantly higher BAG (4.4 ± 6.6 years) compared to HC (Cohen's D = 0.69, p = 4.0 × 10−6). Longitudinal estimates of BAG in MS patients showed high reliability and suggested an accelerated rate of brain aging corresponding to an annual increase of 0.41 (SE = 0.15) years compared to chronological aging (p = 0.008). Multiple regression analyses revealed higher rate of brain aging in patients with more brain atrophy (Cohen's D = 0.86, p = 4.3 × 10−15) and increased white matter lesion load (WMLL) (Cohen's D = 0.55, p = 0.015). On average, patients with MS had significantly higher BAG compared to HC. Progressive brain aging in patients with MS was related to brain atrophy and increased WMLL. No significant clinical associations were found in our sample, future studies are warranted on this matter. Brain age estimation is a promising method for evaluation of subtle brain changes in MS, which is important for predicting clinical outcome and guide choice of intervention

Assessment of cognitive function, structural brain changes and fatigue 6 months after treatment of neuroborreliosis

publishedVersionPaid Open Acces

Is long-bout sedentary behaviour associated with long-term glucose levels 3 months after acute ischaemic stroke? A prospective observational cohort study

Background and purpose Sedentary behaviour is a risk factor for vascular disease and stroke patients are more sedentary than their age-matched peers. The association with glucose levels, as a potential mediator, is unclear, and we have investigated the association between long-bout sedentary behaviour and long-term glucose levels in stroke survivors. Methods This study uses data from the Norwegian Cognitive Impairment After Stroke study, a multicentre cohort study. The patients were recruited at hospital admission for acute stroke, and the follow-up was done at the outpatient clinic. Sedentary behaviour—being in a sitting or reclining position—was registered 3 months after stroke using position transition data from the body-worn sensor activPAL attached to the unaffected thigh. A MATLAB script was developed to extract activity data from 08:00 to 10:00 for 4 days and to categorise the data into four bout-length categories. The primary outcome was glycated haemoglobin (HbA1c), analysed at 3 months. Regression models were used to analyse the association between HbA1c and sedentary behaviour in the whole population and stratified based on a diagnosis of diabetes mellitus (DM). Age, body mass index and the use of antidiabetic drugs were added as covariates into the models. Results From a total of 815 included patients, 379 patients fulfilled the inclusion criteria for this study. We found no association between time in sedentary behaviour and HbA1c in the whole stroke population. We found time in sedentary behaviour in bouts of ≥90 min to be associated with a higher HbA1c in patients with DM. Conclusion Long-bout sedentary time is associated with a higher HbA1c in patients with DM 3 months after ischaemic stroke. Future research should investigate the benefit of breaking up sedentary time as a secondary preventive measure.publishedVersio

Plasma Inflammatory Biomarkers Are Associated With Poststroke Cognitive Impairment: The Nor-COAST Study

Background: Inflammation is proposed to be involved in the pathogenesis of poststroke cognitive impairment. The aim of this study was to investigate associations between concentrations of systemic inflammatory biomarkers after ischemic stroke and poststroke cognitive impairment. Methods: The Nor-COAST study (Norwegian Cognitive Impairment After Stroke) is a prospective observational multicenter cohort study, including patients hospitalized with acute stroke between 2015 and 2017. Inflammatory biomarkers, including the TCC (terminal C5b-9 complement complex) and 20 cytokines, were analyzed in plasma, collected at baseline, 3-, and 18 months poststroke, using ELISA and a multiplex assay. Global cognitive outcome was assessed with the Montreal Cognitive Assessment (MoCA) scale. We investigated the associations between plasma inflammatory biomarkers at baseline and MoCA score at 3-, 18-, and 36-month follow-ups; the associations between inflammatory biomarkers at 3 months and MoCA score at 18- and 36-month follow-ups; and the association between these biomarkers at 18 months and MoCA score at 36-month follow-up. We used mixed linear regression adjusted for age and sex. Results: We included 455 survivors of ischemic stroke. Higher concentrations of 7 baseline biomarkers were significantly associated with lower MoCA score at 36 months; TCC, IL (interleukin)-6, and MIP (macrophage inflammatory protein)-1α were associated with MoCA at 3, 18, and 36 months (P<0.01). No biomarker at 3 months was significantly associated with MoCA score at either 18 or 36 months, whereas higher concentrations of 3 biomarkers at 18 months were associated with lower MoCA score at 36 months (P<0.01). TCC at baseline and IL-6 and MIP-1α measured both at baseline and 18 months were particularly strongly associated with MoCA (P<0.01). Conclusions: Higher concentrations of plasma inflammatory biomarkers were associated with lower MoCA scores up to 36 months poststroke. This was most pronounced for inflammatory biomarkers measured in the acute phase following stroke.publishedVersio

Power estimation for non-standardized multisite studies

AbstractA concern for researchers planning multisite studies is that scanner and T1-weighted sequence-related biases on regional volumes could overshadow true effects, especially for studies with a heterogeneous set of scanners and sequences. Current approaches attempt to harmonize data by standardizing hardware, pulse sequences, and protocols, or by calibrating across sites using phantom-based corrections to ensure the same raw image intensities. We propose to avoid harmonization and phantom-based correction entirely. We hypothesized that the bias of estimated regional volumes is scaled between sites due to the contrast and gradient distortion differences between scanners and sequences. Given this assumption, we provide a new statistical framework and derive a power equation to define inclusion criteria for a set of sites based on the variability of their scaling factors. We estimated the scaling factors of 20 scanners with heterogeneous hardware and sequence parameters by scanning a single set of 12 subjects at sites across the United States and Europe. Regional volumes and their scaling factors were estimated for each site using Freesurfer's segmentation algorithm and ordinary least squares, respectively. The scaling factors were validated by comparing the theoretical and simulated power curves, performing a leave-one-out calibration of regional volumes, and evaluating the absolute agreement of all regional volumes between sites before and after calibration. Using our derived power equation, we were able to define the conditions under which harmonization is not necessary to achieve 80% power. This approach can inform choice of processing pipelines and outcome metrics for multisite studies based on scaling factor variability across sites, enabling collaboration between clinical and research institutions

The Cycad Genotoxin MAM Modulates Brain Cellular Pathways Involved in Neurodegenerative Disease and Cancer in a DNA Damage-Linked Manner

Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of adult C57BL6 wild-type mice treated with a single systemic dose of MAM acetate display DNA damage (O6-methyldeoxyguanosine lesions, O6-mG) that remains constant up to 7 days post-treatment. By contrast, MAM-treated mice lacking a functional gene encoding the DNA repair enzyme O6-mG DNA methyltransferase (MGMT) showed elevated O6-mG DNA damage starting at 48 hours post-treatment. The DNA damage was linked to changes in the expression of genes in cell-signaling pathways associated with cancer, human neurodegenerative disease, and neurodevelopmental disorders. These data are consistent with the established developmental neurotoxic and carcinogenic properties of MAM in rodents. They also support the hypothesis that early-life exposure to MAM-glucoside (cycasin) has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for food or medicine, or both. These findings suggest environmental genotoxins, specifically MAM, target common pathways involved in neurodegeneration and cancer, the outcome depending on whether the cell can divide (cancer) or not (neurodegeneration). Exposure to MAM-related environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer's disease

Thermal decomposition kinetics of the antiparkinson drug “entacapone” under isothermal and non-isothermal conditions

© 2017 Akadémiai Kiadó, Budapest, Hungary The thermal decomposition kinetics of entacapone (ENT) have been investigated via thermogravimetric analysis under non-isothermal and isothermal conditions which provide useful stability information for their processing in the pharmaceutical industry and also for predicting shelf life and suitable storage conditions. The determination of the kinetic parameters for the decomposition process under non-isothermal conditions in a nitrogen atmosphere at four heating rates (5, 10, 15, and 20 °C min −1 ) was performed. Kinetic parameters of the decomposition process for ENT were calculated through Friedman, Flynn–Wall–Ozawa, Kissinger–Akahira–Sunose, and Li–Tang methods. This work demonstrates that the activation energies calculated from the decomposition reactions by different methods are consistent with each other. Moreover, the thermodynamic functions of the decomposition reaction were also calculated