Ambroxol as a novel disease-modifying treatment for Parkinson's disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Currently there are no disease-modifying treatments for Parkinson's disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical and cortical brain areas. One of the leading genetic risk factors for Parkinson's disease is being a carrier in the gene for ß-Glucocerebrosidase (GCase; gene name GBA1). Studies in cell culture and animal models have shown that raising the levels of GCase can decrease levels of α-synuclein. Ambroxol is a pharmacological chaperone for GCase and is able to raise the levels of GCase and could therefore be a disease-modifying treatment for PDD. The aims of this trial are to determine if Ambroxol is safe and well-tolerated by individuals with PDD and if Ambroxol affects cognitive, biochemical, and neuroimaging measures. METHODS: This is a phase II, single-centre, double-blind, randomized placebo-controlled trial involving 75 individuals with mild to moderate PDD. Participants will be randomized into Ambroxol high-dose (1050 mg/day), low-dose (525 mg/day), or placebo treatment arms. Assessments will be undertaken at baseline, 6-months, and 12-months follow up times. Primary outcome measures will be the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician's Global Impression of Change (CGIC). Secondary measures will include the Parkinson's disease Cognitive Rating Scale, Clinical Dementia Rating, Trail Making Test, Stroop Test, Unified Parkinson's disease Rating Scale, Purdue Pegboard, Timed Up and Go, and gait kinematics. Markers of neurodegeneration will include MRI and CSF measures. Pharmacokinetics and pharmacodynamics of Ambroxol will be examined through plasma levels during dose titration phase and evaluation of GCase activity in lymphocytes. DISCUSSION: If found effective and safe, Ambroxol will be one of the first disease-modifying treatments for PDD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02914366, 26 Sep 2016/retrospectively registered.

Vitamin D and white matter abnormalities in older adults: a cross-sectional neuroimaging study.

BACKGROUND AND PURPOSE: Morphological brain changes related to hypovitaminosis D have been poorly studied. In particular, the age-related decrease in vitamin D concentrations may explain the onset of white matter abnormalities (WMA) in older adults. Our objectives were (i) to investigate whether there was an association between serum 25-hydroxyvitamin D (25OHD) concentration and the grade of WMA in older adults and (ii) to determine whether the location of WMA was associated with 25OHD concentration. METHODS: One hundred and thirty-three Caucasian older community-dwellers with no clinical hydrocephalus (mean 71.6 ± 5.6 years; 43.6% female) received a blood test and a magnetic resonance imaging scan of the brain. The grades of total, periventricular and deep WMA were scored using semiquantitative visual rating scales from T2-weighted fluid-attenuated inversion recovery images. The association of WMA with as-measured and deseasonalized 25OHD concentrations was evaluated with the following covariates: age, gender, body mass index, use of anti-vascular drugs, number of comorbidities, impaired mobility, education level, Mini-Mental State Examination score, medial temporal lobe atrophy, serum concentrations of calcium, thyroid-stimulating hormone and vitamin B12, and estimated glomerular filtration rate. RESULTS: Both as-measured and deseasonalized serum 25OHD concentrations were found to be inversely associated with the grade of total WMA (adjusted ß = -0.32, P = 0.027), specifically with periventricular WMA (adjusted ß = -0.15, P = 0.009) but not with deep WMA (adjusted ß = -0.12, P = 0.090). Similarly, participants with 25OHD concentration <75 nM had on average a 33% higher grade of periventricular WMA than those with 25OHD ≥75 nM (P = 0.024). No difference in average grade was found for deep WMA (P = 0.949). CONCLUSIONS: Lower serum 25OHD concentration was associated with higher grade of WMA, particularly periventricular WMA. These findings provide a scientific basis for vitamin D replacement trials.

4-T fMRI of the motor and sensory cortices in patients with polymicrogyria and epilepsy.

OBJECTIVE: Malformations of cortical development (MCD) are an increasingly recognized cause of medically intractable epilepsy. We assessed the role of fMRI in evaluating the motor and somatosensory cortices, as well as if there is possible reorganization of these vital areas in patients with polymicrogyria. METHODS: We included 2 patients with polymicrogyria and epilepsy. Somatosensory and motor cortices were assessed with a 4T fMRI. These findings were compared with direct cortical stimulation. RESULTS: Localization of the sensorimotor cortices was adequately identified by fMRI. These vital areas did not reorganize outside the malformation of cortical development. CONCLUSION: fMRI is a tool that can allow identification of these vital areas of the brain in a non-invasive manner. PRACTICE IMPLICATIONS: Adequate localization of the sensorimotor cortices is important for optimal patient selection, surgical strategy, and to determine the maximal extent of the resection. The clinical implications for such understanding are not limited to it; these findings should help researchers understand more of the neurobiology of MCDs and even possibly clues to the mechanisms of epileptogenesis associated with such malformations.

Slow gait in MCI is associated with ventricular enlargement: results from the Gait and Brain Study.

Slow gait is ubiquitous among older adults and predicts cognitive decline and progression to dementia. Age-related structural brain changes could be responsible for abnormal gait. The purpose of this study was to determine whether brain lateral ventricle volume, a measure of brain atrophy, was associated with gait velocity among older adults with mild cognitive impairment (MCI), while considering the effects of age and brain vascular burden. Twenty community-dwellers with MCI, free of hydrocephalus, aged 76 years (69/80) [median (25th/75th percentile)] (35 % female) from the 'Gait and Brain Study' were included in this analysis. Quantitative gait performance was measured while steady-state walking at self-selected pace with a 6-m electronic portable walkway (GAITRite). Brain ventricle volume was quantified using semi-automated software from three-dimensional T1-weighted magnetic resonance imaging. Age, white matter hyperintensity burden and Mini-Mental State Examination score were used as potential confounders. Median gait velocity was 118.7 cm/s (104.4/131.3). Median brain ventricle volume was 39.9 mL (30.0/46.6) with the left ventricle being slightly larger than the right (P = 0.052). Brain ventricle volume was inversely associated with gait velocity (adjusted ß = -0.63, P = 0.046). Volume of both the ventricular main bodies and the temporal horns correlated inversely with gait velocity (respectively, P = 0.009, P = 0.008). Left ventricle volume correlated with decreased gait velocity (P = 0.002) while right ventricle did not (P = 0.068). Slower gait velocity was associated with larger brain ventricle volume in our sample of people with MCI independent of age, cerebrovascular burden and cognitive worsening. This result may help elucidate the trajectories of cognitive and gait declines in people with MCI.

Reduced hippocampal glutamate in Alzheimer disease.

Altered neurometabolic profiles have been detected in Alzheimer disease (AD) using (1)H magnetic resonance spectroscopy (MRS), but no definitive biomarker of mild cognitive impairment (MCI) or AD has been established. This study used MRS to compare hippocampal metabolite levels between normal elderly controls (NEC) and subjects with MCI and AD. Short echo-time (TE=46 ms) (1)H spectra were acquired at 4T from the right hippocampus of 23 subjects with AD, 12 subjects with MCI and 15 NEC. Absolute metabolite levels and metabolite ratios were compared between groups using a multivariate analysis of covariance (covariates: age, sex) followed by post hoc Tukey's test (p<0.05 significant). Subjects with AD had decreased glutamate (Glu) as well as decreased Glu/creatine (Cr), Glu/myo-inositol (mI), Glu/N-acetylaspartate (NAA), and NAA/Cr ratios compared to NEC. Subjects with AD also had decreased Glu/mI ratio compared to MCI. There were no differences between subjects with MCI and NEC. Therefore, in addition to NAA/Cr, decreased hippocampal Glu may be an indicator of AD.

Brain reorganization in patients with spinal cord compression evaluated using fMRI.

OBJECTIVE: This prospective study characterizes the reorganization that occurs within the primary sensorimotor cortices following decompression of cervical spinal stenosis. METHODS: Twelve right-handed patients with cervical myelopathy underwent blood oxygenation level dependent functional MRI (fMRI) prior to decompression and 6 months following surgery. Ten right-handed controls also underwent fMRI. All subjects performed a finger-tapping paradigm with the right hand. Volume time course data were corrected for temporal serial correlation and % normalized before inclusion in the general linear model. Activation maps were created for each group using a threshold of p < 0.005 with Bonferroni correction. Between-group differences in left hemisphere volume of activation (VOA) were measured along the precentral gyrus (PrCG) and postcentral gyrus (PoCG). Each subject also completed clinical questionnaires. RESULTS: Prior to surgery, patients demonstrated a larger VOA (1.23 cm(3), t(max) = 11.8) in comparison to controls within the PrCG. This difference increased following surgery (2.99 cm(3), t(max) = 13.6). Within the PoCG, controls demonstrated a larger VOA (0.53 cm(3), t(max) = 8.28) than preoperative patients. This difference decreased by 0.12 cm(3) (t(max) = 7.05) following surgery. Preoperatively, patients had a 21.7 cm(3) VOA (t(max) = 29.4) within the sensorimotor cortex with the center of gravity located within Brodmann area (BA) 3. Following surgery, the VOA increased to 23.1 cm(3) (t(max) = 26.1) within BA 3. There were significant improvements in clinical outcomes following surgery. CONCLUSIONS: Spinal cord compression resulted in an increase in volume of activation (VOA) within the precentral gyrus (PrCG) and a loss of VOA within the postcentral gyrus (PoCG) in comparison to controls. Surgical decompression results in cortical reorganization with enlarging VOA within both the PrCG and PoCG.

Low-grade glioma: correlation of short echo time 1H-MR spectroscopy with 23Na MR imaging.

BACKGROUND AND PURPOSE: There is considerable variability in the clinical behavior and treatment response of low-grade (WHO grade II) gliomas. The purpose of this work was to characterize the metabolic profile of low-grade gliomas by using short echo time (1)H-MR spectroscopy and to correlate metabolite levels with MR imaging-measured sodium ((23)Na) signal intensity. Based on previous studies, we hypothesized decreased N-acetylaspartate (NAA) and increased myo-inositol (mIns), choline (Cho), glutamate (Glu), and (23)Na signal intensity in glioma tissue. MATERIALS AND METHODS: Institutional ethics committee approval and informed consent were obtained for all of the subjects. Proton ((1)H-MR) spectroscopy (TR/TE = 2200/46 ms) and sodium ((23)Na) MR imaging were performed at 4T in 13 subjects (6 women and 7 men; mean age, 44 years) with suspected low-grade glioma. Absolute metabolite levels were quantified, and relative (23)Na levels were measured in low-grade glioma and compared with the contralateral side in the same patients. Two-sided Student t tests were used to test for statistical significance. RESULTS: Significant decreases were observed for NAA (P < .001) and Glu (P = .004), and increases were observed for mIns (P = .003), Cho (P = .025), and sodium signal intensity (P < .001) in low-grade glioma tissue. Significant correlations (r(2) > 0.25) were observed between NAA and Glu (P < .05) and between NAA and mIns (P < .01). Significant correlations were also observed between (23)Na signal intensity and NAA (P < .01) and between (23)Na signal intensity and Glu (P < .01). Ratios of NAA/mIns, NAA/(23)Na, and NAA/Cho were altered in glioma tissue (P < .001); however based on the t statistic, NAA/(23)Na (t = 9.6) was the most significant, followed by NAA/mIns (t = 6.1), and NAA/Cho (t = 5.0). CONCLUSION: Although Glu concentration is reduced and mIns concentration is elevated in low-grade glioma tissue, the NAA/(23)Na ratio was the most sensitive indicator of pathologic tissue.

Enhanced mineralization of benzo[a]pyrene in the presence of nonaqueous phase liquids.

Bacterial mineralization of [7-14C]benzo[a]pyrene (BaP) to 14CO2 was enhanced by the presence of nonaqueous phase liquids (NAPLs). Mineralization of BaP was affected differently by different NAPLs, and the mode of enhancement of mineralization by a NAPL most likely occurred by a combination of cometabolic and physical effects. Mineralization was enhanced to the greatest extent when BaP was dissolved in a high-boiling distillation product of diesel fuel.

Spectroscopic lineshape correction by QUECC: combined QUALITY deconvolution and eddy current correction.

Lineshape distortion due to residual eddy currents and magnetic field inhomogeneities are often present in short echo time (1)H spectroscopic data. Lineshape correction methods such as QUALITY deconvolution and eddy current correction (ECC), which use a separate reference spectrum for lineshape correction, have shortcomings when unsuppressed water is chosen as the reference. This paper outlines a method of integrating both techniques to overcome these limitations while still using unsuppressed water as the reference signal. This hybrid lineshape correction technique (QUECC) is demonstrated in vivo using stimulated echo acquisition mode (STEAM) localized 4.0 Tesla data. Metabolite quantification precision increased by an average of 7%-46% compared to QUALITY deconvolution (depending on filtering) and by an average of 6% compared to ECC.

Rapid mineralization of benzo[a]pyrene by a microbial consortium growing on diesel fuel.

A microbial consortium which rapidly mineralized the environmentally persistent pollutant benzo[a]pyrene was recovered from soil. The consortium cometabolically converted [7-(14)C]benzo[a]pyrene to (14)CO(2) when it was grown on diesel fuel, and the extent of benzo[a]pyrene mineralization was dependent on both diesel fuel and benzo[a]pyrene concentrations. Addition of diesel fuel at concentrations ranging from 0.007 to 0.2% (wt/vol) stimulated the mineralization of 10 mg of benzo[a]pyrene per liter 33 to 65% during a 2-week incubation period. When the benzo[a]pyrene concentration was 10 to 100 mg liter(-1) and the diesel fuel concentration was 0.1% (wt/vol), an inoculum containing 1 mg of cell protein per liter (small inoculum) resulted in mineralization of up to 17.2 mg of benzo[a]pyrene per liter in 16 days. This corresponded to 35% of the added radiolabel when the concentration of benzo[a]pyrene was 50 mg liter(-1). A radiocarbon mass balance analysis recovered 25% of the added benzo[a]pyrene solubilized in the culture suspension prior to mineralization. Populations growing on diesel fuel most likely promoted emulsification of benzo[a]pyrene through the production of surface-active compounds. The consortium was also analyzed by PCR-denaturing gradient gel electrophoresis of 16S rRNA gene fragments, and 12 dominant bands, representing different sequence types, were detected during a 19-day incubation period. The onset of benzo[a]pyrene mineralization was compared to changes in the consortium community structure and was found to correlate with the emergence of at least four sequence types. DNA from 10 sequence types were successfully purified and sequenced, and that data revealed that eight of the consortium members were related to the class Proteobacteria but that the consortium also included members which were related to the genera Mycobacterium and Sphingobacterium.

Comparison of the quantification precision of human short echo time (1)H spectroscopy at 1.5 and 4.0 Tesla.

Precise quantification of human in vivo short echo time (1)H spectra remains problematic at clinical field strengths due to broad peak linewidths and low signal-to-noise ratio (SNR). In this study, multiple STEAM spectra (TE = 20 ms, volume = 8 cm(3)) were acquired in a single individual at 1.5 T and 4 T to compare quantification precision. Test-retest STEAM spectra (volume = 1.5 cm(3)) were also acquired from the anterior cingulate and thalamus of 10 individuals at 4.0 T. Metabolite levels were quantified using automated software that incorporated field strength-specific prior knowledge. With the distinct methods of data acquisition, processing, and fitting used in this study, peak height SNR increased approximately 80% while peak linewidth increased by approximately 50% in the 8 cm(3) volumes at 4.0 T compared to 1.5 T, resulting in an average increase in quantification precision of 39%. Metabolite levels from test-retest data (1.5 cm(3) voxels at 4.0 T) were quantified with similar inter- and intraindividual variability. Magn Reson Med 44:185-192, 2000. Published 2000 Wiley-Liss, Inc.

Liquid chromatographic profiles of individual compounds of technical toxaphene.

The elution orders of 20 hexa- to nonachlorobornanes and five hexa- to octachlorocamphenes were studied with normal-phase silica and amino phase HPLC, reversed-phase HPLC, as well as gel-permeation chromatography (GPC). Twenty-one compounds of technical toxaphene (CTTs) are commercially available and four were isolated from environmental samples. Structure-activity relationships and chromatographic properties were deduced from the data sets derived on these LC systems. The retention on silica (low-resolution LC and HPLC) increased with the polarity of the CTTs. The elution order of CTTs on amino normal-phase HPLC was, for the most part, the same as on silica normal-phase HPLC. The degree of chlorination determined the elution order of CTTs on C18 RP-HPLC. CTTs eluted from medium-pressure GPC with decreasing molecular size. Chlorobornanes with dichloro substituents on the six-membered ring eluted after the chloroboranes without geminal chlorine atoms on secondary carbons, indicating that these congeners are larger. Altogether, the results increase the knowledge of complex substance class and may serve as a tool in order to gain further standard components.

Current awareness in NMR in biomedicine

In order to keep subscribers up-to-date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of NMR in biomedicine. Each bibliography is divided into 9 sections: 1 Books, Reviews ' Symposia; 2 General; 3 Technology; 4 Brain and Nerves; 5 Neuropathology; 6 Cancer; 7 Cardiac, Vascular and Respiratory Systems; 8 Liver, Kidney and Other Organs; 9 Muscle and Orthopaedic. Within each section, articles are listed in alphabetical order with respect to author. If, in the preceding period, no publications are located relevant to any one of these headings, that section will be omitted.

Factors affecting the quantification of short echo in-vivo 1H MR spectra: prior knowledge, peak elimination, and filtering.

Short echo 1H in-vivo brain MR spectra are difficult to quantify for several reasons: low signal to noise ratio, the severe overlap of spectral lines, the presence of macromolecule resonances beneath the resonances of interest, and the effect of resonances adjacent to the spectral region of interest (SRI). This paper outlines several different quantification strategies and the effect of each on the precision of in-vivo metabolite measurements. In-vivo spectra were quantified with no operator interaction using a template of prior knowledge determined by mathematically modeling separate in-vitro metabolite spectra. Metabolite level estimates and associated precision were compared before and after the inclusion of macromolecule resonances as part of the prior knowledge, and following two different methods of handling resonances adjacent to the SRI. The effects of rectangular and exponential filters were also investigated. All methods were tested using repeated in-vivo spectra from one individual acquired at 1.5 T using stimulated echo acquisition mode (STEAM, TE = 20 ms) localization. The results showed that the inclusion of macromolecules in the prior knowledge was necessary to obtain metabolite levels consistent with the literature, while the fitting of resonances adjacent to the SRI concurrent with modeled metabolites optimized the precision of metabolite estimates. Metabolite levels and precision were also affected by rectangular and exponential filtering, suggesting caution must be taken when such filters are used.

A short echo proton magnetic resonance spectroscopy study of the left mesial-temporal lobe in first-onset schizophrenic patients.

BACKGROUND: Past 1H magnetic resonance spectroscopy (MRS) studies of the temporal lobe in schizophrenic patients have shown decreased levels of N-acetylaspartate (NAA) suggesting reduced neuronal density in this region. However, the measured volumes have been large and included contributions from mostly white matter. METHODS: Short echo 1H MRS was used to measure levels of NAA and other metabolites (i.e., glutamate and glutamine) from a 6 cm3 volume in the left mesial-temporal lobe of 11 first-episode schizophrenic patients and 11 healthy control subjects of comparable age, gender, handedness, education, and parental education levels. Spectra were quantified without operator interaction using automated software developed in our laboratory. Metabolite levels were normalized to the internal water concentration of each volume studied. Images were also obtained to determine temporal lobe gray and white matter volumes. RESULTS: No significant differences were found between levels of NAA or other metabolites, or gray and white matter volumes, in first-episode schizophrenic patients and comparison subjects. CONCLUSIONS: Since the volume studied was small compared to previous studies and contained mostly gray matter, this result suggests consequential NAA decreases may be restricted to regions of white matter.

Metabolism of benzene, toluene, and xylene hydrocarbons in soil

Enrichment cultures obtained from soil exposed to benzene, toluene, and xylene (BTX) mineralized benzene and toluene but cometabolized only xylene isomers, forming polymeric residues. This observation prompted us to investigate the metabolism of 14C-labeled BTX hydrocarbons in soil, either individually or as mixtures. BTX-supplemented soil was incubated aerobically for up to 4 weeks in a sealed system that automatically replenished any O2 consumed. The decrease in solvent vapors and the production of 14CO2 were monitored. At the conclusion of each experiment, 14C distribution in solvent-extractable polymers, biomass, and humic material was determined, obtaining 14C mass balances of 85 to 98%. BTX compounds were extensively mineralized in soil, regardless of whether they were presented singly or in combinations. No evidence was obtained for the formation of solvent-extractable polymers from xylenes in soil, but 14C distribution in biomass (5 to 10%) and humus (12 to 32%) was unusual for all BTX compounds and especially for toluene and the xylenes. The results suggest that catechol intermediates of BTX degradation are preferentially polymerized into the soil humus and that the methyl substituents of the catechols derived from toluene and especially from xylenes enhance this incorporation. In contrast to inhibitory residues formed from xylene cometabolism in culture, the humus-incorporated xylene residues showed no significant toxicity in the Microtox assay.

A short echo 1H spectroscopy and volumetric MRI study of the corpus striatum in patients with obsessive-compulsive disorder and comparison subjects.

OBJECTIVE: It is likely that the corpus striatum is involved in obsessive-compulsive disorder (OCD). Prior studies have inconsistently found alterations in caudate volumes in patients with OCD. This study was undertaken in the hope that N-acetylaspartate and volumetric measures together would elucidate the presence and nature of corpus striatum volumetric abnormalities in OCD. METHOD: Thirteen patients meeting the DSM-IV criteria for OCD, who had been medication free for a minimum of 6 weeks, and 13 psychiatrically normal matched comparison subjects participated in the study. Short echo 1H magnetic resonance spectroscopy (1H-MRS) was used to measure levels of N-acetylaspartate and several other cerebral metabolites from a 4.5-cm3 volume in the left corpus striatum of all 26 subjects. Metabolite levels were estimated by fitting the time domain spectroscopy data with a noninteractive computer program. Volumes of the left and right head of the caudate nucleus in each subject were determined by semiautomatic segmentation of the volumetric images. RESULTS: N-Acetylaspartate levels from the left corpus striatum were significantly lower in the patients with OCD than in the comparison subjects. There were no differences in either left or right caudate volume between the two groups. CONCLUSIONS: Despite the lack of differences in caudate volumes between the OCD patients and the comparison subjects, the lower level of N-acetylaspartate in the left corpus striatum of the patients suggests reduced neuronal density in this region. Inconsistent volumetric findings among prior studies may reflect a poorer sensitivity of magnetic resonance imaging morphometry for detecting neuronal loss compared with 1H-MRS measurement of N-acetylaspartate.