Antisense Oligonucleotide Silencing Reverses Abnormal Neurochemistry in Spinocerebellar Ataxia 3 Mice.

OBJECTIVE: Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia, and biomarkers are needed to noninvasively monitor disease progression and treatment response. Anti-ATXN3 antisense oligonucleotide (ASO) treatment has been shown to mitigate neuropathology and rescue motor phenotypes in SCA3 mice. Here, we investigated whether repeated ASO administration reverses brainstem and cerebellar neurochemical abnormalities by magnetic resonance spectroscopy (MRS). METHODS: Symptomatic SCA3 mice received intracerebroventricular treatment of ASO or vehicle and were compared to wild-type vehicle-treated littermates. To quantify neurochemical changes in treated mice, longitudinal 9.4T MRS of cerebellum and brainstem was performed. Acquired magnetic resonance (MR) group means were analyzed by 2-way analysis of variance mixed-effects sex-adjusted analysis with post hoc Sidak correlation for multiple comparisons. Pearson correlations were used to relate SCA3 pathology and behavior. RESULTS: MR spectra yielded 15 to 16 neurochemical concentrations in the cerebellum and brainstem. ASO treatment in SCA3 mice resulted in significant total choline rescue and partial reversals of taurine, glutamine, and total N-acetylaspartate across both regions. Some ASO-rescued neurochemicals correlated with reduction in diseased protein and nuclear ATXN3 accumulation. ASO-corrected motor activity correlated with total choline and total N-acetylaspartate levels early in disease. INTERPRETATION: SCA3 mouse cerebellar and brainstem neurochemical trends parallel those in patients with SCA3. Decreased total choline may reflect oligodendrocyte abnormalities, decreased total N-acetylaspartate highlights neuronal health disturbances, and high glutamine may indicate gliosis. ASO treatment fully or partially reversed select neurochemical abnormalities in SCA3 mice, indicating the potential for these measures to serve as noninvasive treatment biomarkers in future SCA3 gene silencing trials. ANN NEUROL 2023;94:658-671.

Neurochemical correlates of synapse density in a Huntington's disease mouse model.

Striatal medium spiny neurons are highly susceptible in Huntington's disease (HD), resulting in progressive synaptic perturbations that lead to neuronal dysfunction and death. Non-invasive imaging techniques, such as proton magnetic resonance spectroscopy (1 H-MRS), are used in HD mouse models and patients with HD to monitor neurochemical changes associated with neuronal health. However, the association between brain neurochemical alterations and synaptic dysregulation remains unknown, limiting our ability to monitor potential treatments that may affect synapse function. We conducted in vivo longitudinal 1 H-MRS in the striatum followed by ex vivo analyses of excitatory synapse density of two synaptic circuits disrupted in HD, thalamo-striatal (T-S), and cortico-striatal (C-S) pathways, to assess the relationship between neurochemical alterations and changes in synapse density. We used the zQ175(Tg/0) HD mouse model as well as zQ175 mice lacking one allele of CK2α'(zQ175(Tg/0) :CK2α'(+/-) ), a kinase previously shown to regulate synapse function in HD. Longitudinal analyses of excitatory synapse density showed early and sustained reduction in T-S synapses in zQ175 mice, preceding C-S synapse depletion, which was rescued in zQ175:CK2α'(+/-) . Changes in T-S and C-S synapses were accompanied by progressive alterations in numerous neurochemicals between WT and HD mice. Linear regression analyses showed C-S synapse number positively correlated with 1 H-MRS-measured levels of GABA, while T-S synapse number positively correlated with levels of phosphoethanolamine and negatively correlated with total creatine levels. These associations suggest that these neurochemical concentrations measured by 1 H-MRS may facilitate monitoring circuit-specific synaptic dysfunction in the zQ175 mouse model and in other HD pre-clinical studies.

Scyllo-inositol: Transverse relaxation time constant at 3 T and concentration changes associated with aging and alcohol use.

The goals of this study were to measure the apparent transverse relaxation time constant, T2 , of scyllo-inositol (sIns) in young and older healthy adults' brains and to investigate the effect of alcohol usage on sIns in young and older healthy adults' brains, using proton magnetic resonance spectroscopy (MRS) at 3 T. Twenty-nine young adults (age 21 ± 1 years) and 24 older adults (age 74 ± 3 years) participated in this study. MRS data were acquired from two brain regions (the occipital cortex and posterior cingulate cortex) at 3 T. The T2 of sIns was measured using a localization by adiabatic selective refocusing (LASER) sequence at various echo times, while the sIns concentrations were measured using a short-echo-time stimulated echo acquisition mode (STEAM) sequence. A trend towards lower T2 relaxation values of sIns in older adults was observed, although these were not significant. sIns concentration was higher with age in both brain regions and was significantly higher in the young when considering alcohol consumption of more than two drinks per week. This study shows that differences in sIns can be found in two distinct regions of the brain across two age groups, potentially reflecting normal aging. In addition, it is important to take into account alcohol consumption when reporting the sIns level in the brain.

Different FreeSurfer versions might generate different statistical outcomes in case-control comparison studies.

PURPOSE: Neuroimaging pipelines have long been known to generate mildly differing results depending on various factors, including software version. While considered generally acceptable and within the margin of reasonable error, little is known about their effect in common research scenarios such as inter-group comparisons between healthy controls and various pathological conditions. The aim of the presented study was to explore the differences in the inferences and statistical significances in a model situation comparing volumetric parameters between healthy controls and type 1 diabetes patients using various FreeSurfer versions. METHODS: T1- and T2-weighted structural scans of healthy controls and type 1 diabetes patients were processed with FreeSurfer 5.3, FreeSurfer 5.3 HCP, FreeSurfer 6.0 and FreeSurfer 7.1, followed by inter-group statistical comparison using outputs of individual FreeSurfer versions. RESULTS: Worryingly, FreeSurfer 5.3 detected both cortical and subcortical volume differences out of the preselected regions of interest, but newer versions such as FreeSurfer 5.3 HCP and FreeSurfer 6.0 reported only subcortical differences of lower magnitude and FreeSurfer 7.1 failed to find any statistically significant inter-group differences. CONCLUSION: Since group averages of individual FreeSurfer versions closely matched, in keeping with previous literature, the main origin of this disparity seemed to lie in substantially higher within-group variability in the model pathological condition. Ergo, until validation in common research scenarios as case-control comparison studies is included into the development process of new software suites, confirmatory analyses utilising a similar software based on analogous, but not fully equivalent principles, might be considered as supplement to careful quality control.

An association between resting state EEG parameters and the severity of topiramate-related cognitive impairment.

INTRODUCTION: Many commonly prescribed drugs cause cognitive deficits. We investigated whether parameters of the resting-state electroencephalogram (rsEEG) are related to the severity of cognitive impairments associated with administration of the antiseizure drug topiramate (TPM) and the benzodiazepine lorazepam (LZP). METHODS: We conducted a double-blind, randomized, placebo-controlled crossover study. After a baseline visit, subjects completed three sessions at which they received either a single dose of TPM, LZP, or placebo. Four-hours after drug administration and at baseline, subjects completed a working memory (WM) task after their rsEEG was recorded. After quantifying drug-related behavioral (WM accuracy (ACC)/reaction time (RT)) and electrophysiological (alpha, theta, beta (1,2), gamma power) change for each subject, we constructed drug-specific mixed effects models of change for each WM and EEG measure. Regression models were constructed to characterize the relationship between baseline rsEEG measures and drug-related performance changes. RESULTS: Linear mixed effects models showed theta power increases in response to TPM administration. The results of the regression models revealed a number of robust relationships between baseline rsEEG parameters and TPM-related, but not LZP-related, WM impairment. CONCLUSIONS: We showed for the first time that parameters of the rsEEG are associated with the severity of TPM-related WM deficits; this suggests that rsEEG measures may have novel clinical applications in the future.

Factors Influencing Electrode Position and Bending of the Proximal Lead in Deep Brain Stimulation for Movement Disorders.

BACKGROUND: The introduction of intracranial air (ICA) during deep brain stimulation (DBS) surgery is thought to have a negative influence on targeting and clinical outcomes. OBJECTIVE: To investigate ICA volumes following surgery and other patient-specific factors as potential variables influencing translocation of the DBS electrode and proximal lead bowing. METHODS: High-resolution postoperative computed tomography scans (≤1.0 mm resolution in all directions) within 24 h following DBS surgery and 4-6 weeks of follow-up were acquired. A total of 50 DBS leads in 33 patients were available for analysis. DBS leads included Abbott/St. Jude Medical InfinityTM, Boston Scientific VerciseTM, and Medtronic 3389TM. RESULTS: Both ICA volume and anatomical target were significantly associated with measures of DBS electrode translocation. ICA volume and DBS lead model were found to be significant predictors of proximal lead bowing. Measures of proximal lead bowing and translocation along the electrode trajectory for the Medtronic 3389TM DBS lead were significantly larger than measures for the Abbott/St. Jude Medical InfinityTM and Boston Scientific VerciseTM DBS leads. CONCLUSION: The association between ICA volume and translocation of the DBS electrode is small in magnitude and not clinically relevant for DBS cases within a normal range of postoperative subdural air volumes. Differences in proximal lead bowing observed between DBS leads may reflect hardware engineering subtleties in the construction of DBS lead models.

Neurochemical abnormalities in premanifest and early spinocerebellar ataxias.

OBJECTIVE: To investigate whether early neurochemical abnormalities are detectable by high-field magnetic resonance spectroscopy (MRS) in individuals with spinocerebellar ataxias (SCAs) 1, 2, 3, and 6, including patients without manifestation of ataxia. METHODS: A cohort of 100 subjects (N = 18-21 in each SCA group, including premanifest mutation carriers; mean score on the Scale for the Assessment and Rating of Ataxia [SARA] <10 for all genotypes, and 22 matched controls) was scanned at 7 Tesla to obtain neurochemical profiles of the cerebellum and brainstem. A novel multivariate approach (distance-weighted discrimination) was used to combine regional profiles into an "MRS score." RESULTS: MRS scores robustly distinguished individuals with SCA from controls, with misclassification rates of 0% (SCA2), 2% (SCA3), 5% (SCA1), and 17% (SCA6). Premanifest mutation carriers with estimated disease onset within 10 years had MRS scores in the range of early-manifest SCA subjects. Levels of neuronal and glial markers significantly correlated with SARA and an Activities of Daily Living score in subjects with SCA. Regional neurochemical alterations were different between SCAs at comparable disease severity, with SCA2 displaying the most extensive neurochemical abnormalities, followed by SCA1, SCA3, and SCA6. INTERPRETATION: Neurochemical abnormalities are detectable in individuals before manifest disease, which may allow premanifest enrollment in future SCA trials. Correlations with ataxia and quality-of-life scores show that neurochemical levels can serve as clinically meaningful endpoints in trials. Ranking of SCA types by degree of neurochemical abnormalities indicates that the neurochemistry may reflect synaptic function or density. Ann Neurol 2018;83:816-829.

Neurochemical correlates of functional decline in amyotrophic lateral sclerosis.

OBJECTIVE: To determine whether proton magnetic resonance spectroscopy (1H-MRS) can detect neurochemical changes in amyotrophic lateral sclerosis (ALS) associated with heterogeneous functional decline. METHODS: Nineteen participants with early-stage ALS and 18 age-matched and sex ratio-matched controls underwent ultra-high field 1H-MRS scans of the upper limb motor cortex and pons, ALS Functional Rating Scale-Revised (ALSFRS-R total, upper limb and bulbar) and upper motor neuron burden assessments in a longitudinal observational study design with follow-up assessments at 6 and 12 months. Slopes of neurochemical levels over time were compared between patient subgroups classified by the rate of upper limb or bulbar functional decline. 1H-MRS and clinical ratings at baseline were assessed for ability to predict study withdrawal due to disease progression. RESULTS: Motor cortex total N-acetylaspartate to myo-inositol ratio (tNAA:mIns) significantly declined in patients who worsened in upper limb function over the follow-up period (n=9, p=0.002). Pons glutamate + glutamine significantly increased in patients who worsened in bulbar function (n=6, p<0.0001). Neurochemical levels did not change in patients with stable function (n=5-6) or in healthy controls (n=14-16) over time. Motor cortex tNAA:mIns and ALSFRS-R at baseline were significantly lower in patients who withdrew from follow-up due to disease progression (n=6) compared with patients who completed the 12-month scan (n=10) (p<0.001 for tNAA:mIns; p<0.01 for ALSFRS-R), with a substantially larger overlap in ALSFRS-R between groups. CONCLUSION: Neurochemical changes in motor areas of the brain are associated with functional decline in corresponding body regions. 1H-MRS was a better predictor of study withdrawal due to ALS progression than ALSFRS-R.

Oxygen consumption deficit in Huntington disease mouse brain under metabolic stress.

In vivo evidence for brain mitochondrial dysfunction in animal models of Huntington disease (HD) is scarce. We applied the novel 17O magnetic resonance spectroscopy (MRS) technique on R6/2 mice to directly determine rates of oxygen consumption (CMRO2) and assess mitochondrial function in vivo Basal respiration and maximal CMRO2 in the presence of the mitochondrial uncoupler dinitrophenol (DNP) were compared using 16.4 T in isoflurane anesthetized wild type (WT) and HD mice at 9 weeks. At rest, striatal CMRO2 of R6/2 mice was equivalent to that of WT, indicating comparable mitochondrial output despite onset of motor symptoms in R6/2. After DNP injection, the maximal CMRO2 in both striatum and cortex of R6/2 mice was significantly lower than that of WT, indicating less spare energy generating capacity. In a separate set of mice, oligomycin injection to block ATP generation decreased CMRO2 equally in brains of R6/2 and WT mice, suggesting oxidative phosphorylation capacity and respiratory coupling were equivalent at rest. Expression levels of representative mitochondrial proteins were compared from harvested tissue samples. Significant differences between R6/2 and WT included: in striatum, lower VDAC and the mitochondrially encoded cytochrome oxidase subunit I relative to actin; in cortex, lower tricarboxylic acid cycle enzyme aconitase and higher protein carbonyls; in both, lower glycolytic enzyme enolase. Therefore in R6/2 striatum, lowered CMRO2 may be attributed to a decrease in mitochondria while the cortical CMRO2 decrease may result from constraints upstream in energetic pathways, suggesting regionally specific changes and possibly rates of metabolic impairment.

Discriminating sample groups with multi-way data.

High-dimensional linear classifiers, such as distance weighted discrimination (DWD) and versions of the support vector machine (SVM), are commonly used in biomedical research to distinguish groups of subjects based on a large number of features. However, their use is limited to applications where a single vector of features is measured for each subject. In practice, data are often multi-way, or measured over multiple dimensions. For example, metabolite abundance may be measured over multiple regions or tissues, or gene expression may be measured over multiple time points, for the same subjects. We propose a framework for linear classification of high-dimensional multi-way data, in which coefficients can be factorized into weights that are specific to each dimension. More generally, the coefficients for each measurement in a multi-way dataset are assumed to have low-rank structure. This framework extends existing classification techniques from single vector to multi-way features, and we have implemented multi-way versions of SVM and DWD. We describe informative simulation results, and apply multi-way DWD to data for two very different clinical research studies. The first study uses magnetic resonance spectroscopy metabolite data over multiple brain regions to compare participants with and without spinocerebellar ataxia; the second uses publicly available gene expression time-course data to compare degrees of treatment response among patients with multiple sclerosis. Our multi-way method can improve performance and simplify interpretation over naive applications of full rank linear and non-linear classification to multi-way data. The R package is available at https://github.com/lockEF/MultiwayClassification.

Establishing the overlap of IONP quantification with echo and echoless MR relaxation mapping.

PURPOSE: Iron-oxide nanoparticles (IONPs) have shown tremendous utility for enhancing image contrast and delivering targeted therapies. Quantification of IONPs has been demonstrated at low concentrations with gradient echo (GRE) and spin echo (SE), and at high concentrations with echoless sequences such as swept imaging with Fourier transform (SWIFT). This work examines the overlap of IONP quantification with GRE, SE, and SWIFT. METHODS: The limit of quantification of GRE, SE, inversion-recovery GRE, and SWIFT sequences was assessed using IONPs at a concentration range of 0.02 to 89.29 mM suspended in 1% agarose. Empirically derived limits of quantification were compared with International Union of Pure and Applied Chemistry definitions. Both commercial and experimental IONPs were used. RESULTS: All three IONPs assessed demonstrated an overlap of concentration quantification with GRE, SE, and SWIFT sequences. The largest dynamic range observed was 0.004 to 35.7 mM with Feraheme. CONCLUSIONS: The metrics established allow upper and lower quantitative limitations to be estimated given the relaxivity characteristics of the IONP and the concentration range of the material to be assessed. The methods outlined in this paper are applicable to any pulse sequence, IONP formulation, and field strength. Magn Reson Med 79:1420-1428, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Investigating the physiological effects of 10.5 Tesla static field exposure on anesthetized swine.

PURPOSE: In this work, we investigated the relative effects of static magnetic field exposure (10.5 Tesla [T]) on two physiological parameters; blood pressure (BP) and heart rate (HR). METHODS: In vivo, we recorded both BP and HR in 4 swine (3 female, 1 male) while they were positioned within a 10.5T magnet. All measurements were performed invasively within these anesthetized animals by the placement of pressure catheters into their carotid arteries. RESULTS: We measured average increases of 2.0 mm Hg (standard deviation [SD], 6.9) in systolic BP and an increase of 4.5 mm Hg (SD, 13.7) in the diastolic BPs: We also noted an average increase of 1.2 beats per minute (SD, 2.5) in the HRs during such. CONCLUSION: Data regarding changes in BP and HR in anesthetized swine attributed to whole-body 10.5T exposure are reported. Magn Reson Med 79:511-514, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Individual Differences in Working Memory Capacity Predict Topiramate-Related Cognitive Deficits.

PURPOSE/BACKGROUND: Topiramate (TPM) and lorazepam (LZP) are two examples of frequently prescribed medications that are associated with a high incidence of cognitive impairment; however, the factors that underlie interindividual differences in side effect profiles have not been fully characterized. Our objective was to determine whether working memory capacity (WMC), the amount of information that can be stored and manipulated in memory over short time intervals, is one such factor. METHODS/PROCEDURES: Twenty-nine healthy volunteers completed a double-blind, randomized, placebo-controlled crossover study during which they received placebo (PBO), TPM, and LZP in random order. Four hours after drug administration, a blood draw was taken to establish drug concentrations, and subjects performed a verbal working memory task while the accuracy and reaction time of their responses were recorded. Working memory capacity was calculated based on accuracy rates during the PBO session, and the role of WMC in moderating the severity of drug-related cognitive impairment was assessed by examining drug-related performance changes from PBO as a function of WMC. FINDINGS/RESULTS: Both TPM and LZP had a negative impact on task performance, although only TPM-related deficits were modulated by WMC; high WMC was associated with more severe impairments and heightened sensitivity to increasing TPM concentrations. IMPLICATIONS/CONCLUSIONS: We have identified a potential clinical risk factor, high WMC, which is associated with drug-related adverse cognitive events. These data provide objective evidence in support of clinical observations that high-functioning patients are more likely to experience severe cognitive impairments.

Time to and predictors of dual incontinence in older nursing home admissions.

AIMS: There are few studies of nursing home residents that have investigated the development of dual incontinence, perhaps the most severe type of incontinence as both urinary and fecal incontinence occur. To determine the time to and predictors of dual incontinence in older nursing home residents. METHODS: Using a cohort design, records of older nursing home admissions who were continent or had only urinary or only fecal incontinence (n = 39,181) were followed forward for report of dual incontinence. Four national US datasets containing potential predictors at multiple levels describing characteristics of nursing home residents, nursing homes (n = 445), and socioeconomic and sociodemographic status of the community surrounding nursing homes were analyzed. A Cox proportional hazard regression with nursing home-specific random effect was used. RESULTS: At 6 months after admission, 28% of nursing home residents developed dual incontinence, at 1 year 42% did so, and at 2 years, 61% had dual incontinence. Significant predictors for time to developing dual incontinence were having urinary incontinence, greater functional or cognitive deficits, more comorbidities, older age, and lesser quality of nursing home care. CONCLUSIONS: The development of dual incontinence is a major problem among nursing home residents. Predictors in this study offer guidance in developing interventions to prevent and reduce the time to developing this problem which may improve the quality of life of nursing residents.

Fast, fully Bayesian spatiotemporal inference for fMRI data.

We propose a spatial Bayesian variable selection method for detecting blood oxygenation level dependent activation in functional magnetic resonance imaging (fMRI) data. Typical fMRI experiments generate large datasets that exhibit complex spatial and temporal dependence. Fitting a full statistical model to such data can be so computationally burdensome that many practitioners resort to fitting oversimplified models, which can lead to lower quality inference. We develop a full statistical model that permits efficient computation. Our approach eases the computational burden in two ways. We partition the brain into 3D parcels, and fit our model to the parcels in parallel. Voxel-level activation within each parcel is modeled as regressions located on a lattice. Regressors represent the magnitude of change in blood oxygenation in response to a stimulus, while a latent indicator for each regressor represents whether the change is zero or non-zero. A sparse spatial generalized linear mixed model captures the spatial dependence among indicator variables within a parcel and for a given stimulus. The sparse SGLMM permits considerably more efficient computation than does the spatial model typically employed in fMRI. Through simulation we show that our parcellation scheme performs well in various realistic scenarios. Importantly, indicator variables on the boundary between parcels do not exhibit edge effects. We conclude by applying our methodology to data from a task-based fMRI experiment.

Ultra-High Field Proton MR Spectroscopy in Early-Stage Amyotrophic Lateral Sclerosis.

A major hurdle in the development of effective treatments for amyotrophic lateral sclerosis (ALS) has been the lack of robust biomarkers for use as clinical trial endpoints. Neurochemical profiles obtained in vivo by high field proton magnetic resonance spectroscopy (1H-MRS) can potentially provide biomarkers of cerebral pathology in ALS. However, previous 1H-MRS studies in ALS have produced conflicting findings regarding alterations in the levels of neurochemical markers such as glutamate (Glu) and myo-inositol (mIns). Furthermore, very few studies have investigated the neurochemical abnormalities associated with ALS early in its course. In this study, we measured neurochemical profiles using single-voxel 1H-MRS at 7 T (T) and glutathione (GSH) levels using edited MRS at 3 T in 19 subjects with ALS who had relatively high functional status [ALS Functional Rating Scale-Revised (ALSFRS-R) mean ± SD = 39.8 ± 5.6] and 17 healthy controls. We observed significantly lower total N-acetylaspartate over mIns (tNAA/mIns) ratio in the motor cortex and pons of subjects with ALS versus healthy controls. No group differences were detected in GSH at 3 and 7 T. In subjects with ALS, the levels of tNAA, mIns, and Glu in the motor cortex were dependent on the extent of disease represented by El Escorial diagnostic subcategories. Specifically, combined probable/definite ALS had lower tNAA than possible ALS and controls (both p = 0.03), higher mIns than controls (p < 0.01), and lower Glu than possible ALS (p < 0.01). The effect of disease stage on MRS-measured metabolite levels may account for dissimilar findings among previous 1H-MRS studies in ALS.

Racial disparities in primary prevention of incontinence among older adults at nursing home admission.

AIMS: Maintaining continence of nursing home (NH) residents promotes dignity and well-being and may reduce morbidity and healthcare treatment costs. To determine the prevalence of older continent adults who received primary prevention of incontinence at NH admission, assess whether there were racial or ethnic disparities in incontinence prevention, and describe factors associated with any disparities. METHODS: The design was an observational cross-sectional study of a nation-wide cohort of older adults free of incontinence at NH admission (n = 42,693). Four US datasets describing NH and NH resident characteristics, practitioner orders for NH treatment/care, and socioeconomic and sociodemographic status of the community surrounding the NHs were analyzed. Disparities were analyzed for four minority groups identified on the minimum data set using the Peters-Belson method and covariates at multiple levels. RESULTS: Twelve percent of NH admissions received incontinence prevention. There was a significant disparity (2%) in incontinence prevention for Blacks (P < 0.05): Fewer Black admissions (8.6%) were observed to receive incontinence prevention than was expected had they been part of the White group (10.6%). The percentage of White admissions receiving incontinence prevention was 10.6%. Significant factors associated with disparity in receiving incontinence prevention were having greater deficits in ADL function and cognition and more comorbidities. No disparity disadvantaging the other minority groups was found. CONCLUSIONS: Greater efforts for instituting incontinence prevention at the time of NH admission are needed. Eliminating racial disparities in incontinence prevention seems an attainable goal. Appropriate staff training, organizational commitment, and monitoring progress toward equitable outcomes can help achieve this goal. Neurourol. Urodynam. 36:1124-1130, 2017. © 2016 Wiley Periodicals, Inc.

Incidence and Predictors of Incontinence-Associated Skin Damage in Nursing Home Residents With New-Onset Incontinence.

PURPOSE: The purpose of this study was to determine the incidence and predictors of incontinence-associated dermatitis (IAD) in nursing home residents. METHODS: Records of a cohort of 10,713 elderly (≥65 years) newly incontinent nursing home residents in 448 nursing homes in 28 states free of IAD were followed up for IAD development. Potential multilevel predictors of IAD were identified in 4 national datasets containing information about the characteristics of individual nursing home residents, nursing home care environment, and communities in which the nursing homes were located. A unique set of health practitioner orders provided information about IAD and the predictors of IAD prevention and pressure injuries in the extended perineal area. Analysis was based on hierarchical logistical regression. RESULTS: The incidence of IAD was 5.5%. Significant predictors of IAD were not receiving preventive interventions for IAD, presence of a perineal pressure injury, having greater functional limitations in activities of daily living, more perfusion problems, and lesser cognitive deficits. CONCLUSION: Findings highlight the importance of prevention of IAD and treatment/prevention of pressure injuries. A WOC nurse offers expertise in these interventions and can educate staff about IAD predictors, which can improve resident outcomes. Other recommendations include implementing plans of care to improve functional status, treat perfusion problems, and provide assistance with incontinence and skin care to residents with milder as well as greater cognitive deficits.

Test-retest reproducibility of neurochemical profiles with short-echo, single-voxel MR spectroscopy at 3T and 7T.

PURPOSE: To determine the test-retest reproducibility of neurochemical concentrations obtained with a highly optimized, short-echo, single-voxel proton MR spectroscopy (MRS) pulse sequence at 3T and 7T using state-of-the-art hardware. METHODS: A semi-LASER sequence (echo time = 26-28 ms) was used to acquire spectra from the posterior cingulate and cerebellum at 3T and 7T from six healthy volunteers who were scanned four times weekly on both scanners. Spectra were quantified with LCModel. RESULTS: More neurochemicals were quantified with mean Cramér-Rao lower bounds (CRLBs) ≤20% at 7T than at 3T despite comparable frequency-domain signal-to-noise ratio. Whereas CRLBs were lower at 7T (P < 0.05), between-session coefficients of variance (CVs) were comparable at the two fields with 64 transients. Five metabolites were quantified with between-session CVs ≤5% at both fields. Analysis of subspectra showed that a minimum achievable CV was reached with a lower number of transients at 7T for multiple metabolites and that between-session CVs were lower at 7T than at 3T with fewer than 64 transients. CONCLUSION: State-of-the-art MRS methodology allows excellent reproducibility for many metabolites with 5-min data averaging on clinical 3T hardware. Sensitivity and resolution advantages at 7T are important for weakly represented metabolites, short acquisitions, and small volumes of interest. Magn Reson Med 76:1083-1091, 2016. © 2015 Wiley Periodicals, Inc.

Assessing recovery from neurodegeneration in spinocerebellar ataxia 1: Comparison of in vivo magnetic resonance spectroscopy with motor testing, gene expression and histology.

Suppression of transgene expression in a conditional transgenic mouse model of spinocerebellar ataxia 1 (SCA1) reverses the Purkinje cell pathology and motor dysfunction that are hallmarks of SCA1. We previously showed that cerebellar neurochemical levels measured by magnetic resonance spectroscopy (MRS) correlate with progression of pathology and clinical status of patients and that abnormal neurochemical levels normalize upon suppression of transgene expression, indicating their potential as robust surrogate markers of treatment effects. Here we investigated the relative sensitivities of MRS, histology, transgene expression and motor behavioral testing to disease reversal in conditional SCA1 mice. Transgene expression was suppressed by doxycycline administration and treated and untreated mice were assessed by MRS at 9.4tesla before and after treatment and with an accelerating Rotarod, histology and quantitative polymerase chain reaction (qPCR) for ataxin-1 transgene expression following doxycycline treatment. The MRS-measured N-acetylaspartate-to-myo-inositol ratio (NAA/Ins) correlated significantly with the molecular layer (ML) thickness and transgene expression. NAA/Ins, ML thickness and transgene expression were highly significantly different between the treated vs. untreated groups (p<0.0001), while the Rotarod assessment showed a trend for treatment effect. MRS, qPCR and histology had high sensitivity/specificity to distinguish treated from untreated mice, all with areas under the curve (AUC)=0.97-0.98 in receiver operating characteristic (ROC) analyses, while Rotarod had significantly lower sensitivity and specificity (AUC=0.72). Therefore, MRS accurately reflects the extent of recovery from neurodegeneration with sensitivity similar to invasive measures, further validating its potential as a surrogate marker in pre-clinical and clinical treatment trials.