帕金森病大鼠未注射侧纹状体和黑质酪氨酸羟化酶的表达

目的:观察不同病程偏侧帕金森病(PD)大鼠未注射侧纹状体和黑质酪氨酸羟化酶(TH)的表达.方法:6-羟基多巴胺(6-OHDA)右侧前脑内侧束立体定位注射1周,阿朴吗啡旋转实验筛选PD模型大鼠,随机分为2、4周和6周模型组,另设正常对照组.行嘴侧纹状体节段和黑质节段连续冠状石蜡切片,采用焦油紫染色定位,以TH抗体免疫组织化学阳性显示多巴胺(DA)能神经元胞体和纤维.结果:正常对照组和2周模型组大鼠左侧纹状体有较强的TH表达,而4周和6周模型组左侧纹状体的TH表达强度较上述两组降低,4周和6周模型组之间无差异.4组大鼠左侧黑质TH表达阳性细胞数无差异.正常对照组、2周和4周模型组左侧黑质有较强的TH表达,3组的表达强度无差异,而6周模型组左侧黑质的TH表达强度较上述3组均降低.结论:6-OHDA单侧注射制备的PD模型大鼠,注射侧的长期病变致未注射侧纹状体和黑质TH的表达减弱.     

Assessment of metabolic changes in the striatum of a rat model of parkinsonism: an in vivo 1H MRS study

Degeneration of the dopaminergic neurons of the substantia nigra pars compacta in Parkinson's disease induces an abnormal activation of the glutamatergic neurotransmission system within the basal ganglia network and related structures. The aim of this study was to use proton MRS to show metabolic changes in the striatum of 6‐hydroxydopamine‐lesioned rats, a rodent animal model of Parkinson's disease. Animals were examined before and after extensive lesioning of the nigral dopaminergic neurons and after acute administration of L ‐3,4‐dihydroxyphenylalanine. No significant alterations in glutamate concentrations, assessed by the MR signal dominated by glutamate with minor contributions from glutamine and γ‐aminobutyric acid, could be measured. The total choline/total creatine ratio was found to be reduced in the striatum of the ipsilateral hemisphere. Copyright © 2008 John Wiley & Sons, Ltd.     

Alterations in the histaminergic system in the substantia nigra and striatum of Parkinson's patients: a postmortem study

Earlier studies showed neuronal histamine production in the hypothalamic tuberomamillary nucleus to be unchanged in Parkinson's disease (PD), whereas the histamine levels and innervation in the substantia nigra (SN) increased. In the present study we used quantitative polymerase chain reaction (qPCR) to assess the changes in the histaminergic system in the SN, caudate nucleus (CN), and putamen (PU) in 7 PD patients and 7 controls. The messenger RNA (mRNA) expression of the histamine receptor-3 (H(3)R), which was localized immunocytochemically in the large pigmented neurons, was significantly decreased in the SN in PD, while histamine receptor-4 (H(4)R)-mRNA expression showed a significant increase in caudate nucleus and PU. In addition, significantly increased mRNA levels of histamine methyltransferase (HMT), a key enzyme involved in histamine metabolism, were found in the SN and in the PU in PD. Moreover, in the SN, the histamine methyltransferase-mRNA showed a strong negative correlation with PD disease duration. Our observations imply the presence of local changes in the histaminergic system that may contribute to PD pathology, and may thus provide a rationale for possible novel therapeutic strategies.     

Complementarity of gluCEST and 1H‐MRS for the study of mouse models of Huntington's disease

Identification of relevant biomarkers is fundamental to understand biological processes of neurodegenerative diseases and to evaluate therapeutic efficacy. Atrophy of brain structures has been proposed as a biomarker, but it provides little information about biochemical events related to the disease. Here, we propose to identify early and relevant biomarkers by combining biological specificity provided by ¹H‐MRS and high spatial resolution offered by gluCEST imaging. For this, two different genetic mouse models of Huntington's disease (HD)—the Ki140CAG model, characterized by a slow progression of the disease, and the R6/1 model, which mimics the juvenile form of HD—were used. Animals were scanned at 11.7 T using a protocol combining ¹H‐MRS and gluCEST imaging. We measured a significant decrease in levels of N‐acetyl‐aspartate, a metabolite mainly located in the neuronal compartment, in HD animals, and the decrease seemed to be correlated with disease severity. In addition, variations of tNAA levels were correlated with striatal volumes in both models. Significant variations of glutamate levels were also observed in Ki140CAG but not in R6/1 mice. Thanks to its high resolution, gluCEST provided complementary insights, and we highlighted alterations in small brain regions such as the corpus callosum in Ki140CAG mice, whereas the glutamate level was unchanged in the whole brain of R6/1 mice. In this study, we showed that ¹H‐MRS can provide key information about biological processes occurring in vivo but was limited by the spatial resolution. On the other hand, gluCEST may finely point to alterations in unexpected brain regions, but it can also be blind to disease processes when glutamate levels are preserved. This highlights in a practical context the complementarity of the two methods to study animal models of neurodegenerative diseases and to identify relevant biomarkers.     

Altered Expression of Growth Associated Protein‐43 and Rho Kinase in Human Patients with Parkinson's Disease

Causative treatment strategies for Parkinson's disease (PD) will have to address multiple underlying pathomechanisms to attenuate neurodegeneration. Additionally, the intrinsic regenerative capacity of the central nervous system is also an important factor contributing to restoration. Extracellular cues can limit sprouting and regrowth of adult neurons, but even aged neurons have a low intrinsic regeneration capacity. Whether this capacity has been lost or if growth inhibitory cues are increased during PD progression has not been resolved yet. In this study, we assessed the regenerative potential in the nigrostriatal system in post‐mortem brain sections of PD patients compared to age‐matched and young controls. Investigation of the expression pattern of the regeneration‐associated protein GAP‐43 suggested a lower regenerative capacity in nigral dopaminergic neurons of PD patients. Furthermore, the increase in protein expression of the growth‐inhibitory protein ROCK2 in astrocytes and a similar trend in microglia, suggests an important role for ROCK2 in glial PD pathology, which is initiated already in normal aging. Considering the role of astro‐ and microglia in PD pathogenesis as well as beneficial effects of ROCK inhibition on neuronal survival and regeneration in neurodegenerative disease models, our data strengthens the importance of the ROCK pathway as a therapeutic target in PD.     

An in vivo ultrahigh field 14.1 T 1H‐MRS study on 6‐OHDA and α‐synuclein‐based rat models of Parkinson's disease: GABA as an early disease marker

The detection of Parkinson's disease (PD) in its preclinical stages prior to outright neurodegeneration is essential to the development of neuroprotective therapies and could reduce the number of misdiagnosed patients. However, early diagnosis is currently hampered by lack of reliable biomarkers. ¹H magnetic resonance spectroscopy (MRS) offers a noninvasive measure of brain metabolite levels that allows the identification of such potential biomarkers. This study aimed at using MRS on an ultrahigh field 14.1 T magnet to explore the striatal metabolic changes occurring in two different rat models of the disease. Rats lesioned by the injection of 6‐hydroxydopamine (6‐OHDA) in the medial‐forebrain bundle were used to model a complete nigrostriatal lesion while a genetic model based on the nigral injection of an adeno‐associated viral (AAV) vector coding for the human α‐synuclein was used to model a progressive neurodegeneration and dopaminergic neuron dysfunction, thereby replicating conditions closer to early pathological stages of PD. MRS measurements in the striatum of the 6‐OHDA rats revealed significant decreases in glutamate and N‐acetyl‐aspartate levels and a significant increase in GABA level in the ipsilateral hemisphere compared with the contralateral one, while the αSyn overexpressing rats showed a significant increase in the GABA striatal level only. Therefore, we conclude that MRS measurements of striatal GABA levels could allow for the detection of early nigrostriatal defects prior to outright neurodegeneration and, as such, offers great potential as a sensitive biomarker of presymptomatic PD. Copyright © 2012 John Wiley & Sons, Ltd.     

Intra‐ and interindividual variability of fatty acid unsaturation in six different human adipose tissue compartments assessed by 1H‐MRS in vivo at 3 T

It is generally accepted that the amount and distribution of adipose tissue (AT) in the human body play an important role in the pathogenesis of metabolic diseases. In addition, metabolic effects of released saturated fatty acids (FAs) in blood are known to be more critical than those of unsaturated FAs. However, little is known about the variability in unsaturation of FAs in various AT compartments. The aim of this prospective study was the assessment of mono‐ and polyunsaturated FAs in various AT compartments by localized ¹H‐MRS in order to obtain insight into the intra‐ and interindividual variability. Associations of FA unsaturation with intrahepatic lipids (IHLs), insulin sensitivity and related AT volumes were analyzed. Fifty healthy Caucasians (36 male, 14 female) participated in this study. Spectroscopic examinations were performed in subcutaneous adipose tissue in the neck (SCAT_neck), abdominal deep subcutaneous adipose tissue (DSCAT), abdominal superficial subcutaneous adipose tissue (SSCAT), visceral adipose tissue (VAT), tibial bone marrow (BM) and subcutaneous adipose tissue of the lower leg (SCAT_calf) at 3 T. Unsaturated index (UI) was calculated by the ratio of olefinic and methyl resonances, polyunsaturated index (PUI) by the ratio of diallylic and methyl resonances. Volumes of AT compartments (by T₁‐weighted MRI) and IHL (single‐voxel STEAM) were assessed at 1.5 T, insulin sensitivity by an oral glucose tolerance test. UI was highest for SCAT_calf (0.622) and lowest for BM (0.527). Highest PUI was observed for SSCAT (0.108), lowest for BM (0.093). Significant intraindividual differences between UIs—but not PUIs—are present for most compartments. There is a non‐significant trend for higher UI in males but otherwise no correlation to anthropometric data (age, BMI). A significant negative correlation between UI and AT volume was observed for VAT but for none of the other compartments. Neither UIs nor PUIs show a relation with IHL; insulin sensitivity is significantly correlated to UI in BM (p < 0.01). Unsaturation indices in several distinct AT compartments are location dependent. Our cohort showed only moderate gender‐related differences, with a trend towards less unsaturated FAs (mainly PUI) in females. In BM, insulin resistant subjects are characterized by a higher UI compared with the insulin sensitive ones. Further studies in larger cohorts are necessary to gain further insight into unsaturation of AT.     

Abnormal levels of prohibitin and ATP synthase in the substantia nigra and frontal cortex in Parkinson's disease

Prohibitin and ATP synthase protein levels were examined in the substantia nigra and frontal cortex (area 8) in five cases of Parkinson's disease (PD), five cases of dementia with Lewy bodies pure form (pDLB), five cases of early Alzheimer's disease (AD stage IIA, B), nine cases with advanced AD (stages V/VIC), and nine controls. A significant reduction of prohibitin and ATP synthase was observed in the substantia nigra in PD cases. In contrast, increased prohibitin and ATP synthase levels were found in the frontal cortex in PD, and increased prohibitin but not ATP synthase in the frontal cortex in pDLB. Superoxide dismutase 2 (SOD2) expression levels were also increased in the frontal cortex in PD and pDLB. No modifications in prohibitin and ATP synthase levels were found in the frontal cortex in sporadic AD. These findings demonstrate disease-specific modifications in the expression of mitochondrial-related proteins in the frontal cortex at stages of PD in which there is no alpha-synuclein aggregation in the form of Lewy bodies and Lewy neurites in this area. These findings emphasize the presence of mitochondrial modifications before the appearance of histological hallmarks of PD, and point to the possibility of a more extended molecular pathology in PD than currently accepted.     

Global gray and white matter metabolic changes after simian immunodeficiency virus infection in CD8‐depleted rhesus macaques: proton MRS imaging at 3 T

To test the hypotheses that global decreased neuro‐axonal integrity reflected by decreased N‐acetylaspartate (NAA) and increased glial activation reflected by an elevation in its marker, the myo‐inositol (mI), present in a CD8‐depleted rhesus macaque model of HIV‐associated neurocognitive disorders. To this end, we performed quantitative MRI and 16 × 16 × 4 multivoxel proton MRS imaging (TE/TR = 33/1400 ms) in five macaques pre‐ and 4–6 weeks post‐simian immunodeficiency virus infection. Absolute NAA, creatine, choline (Cho), and mI concentrations, gray and white matter (GM and WM) and cerebrospinal fluid fractions were obtained. Global GM and WM concentrations were estimated from 224 voxels (at 0.125 cm³ spatial resolution over ~35% of the brain) using linear regression. Pre‐ to post‐infection global WM NAA declined 8%: 6.6 ± 0.4 to 6.0 ± 0.5 mM (p = 0.05); GM Cho declined 20%: 1.3 ± 0.2 to 1.0 ± 0.1 mM (p < 0.003); global mI increased 11%: 5.7 ± 0.4 to 6.5 ± 0.5 mM (p < 0.03). Global GM and WM brain volume fraction changes were statistically insignificant. These metabolic changes are consistent with global WM (axonal) injury and glial activation, and suggest a possible GM host immune response. Copyright © 2013 John Wiley & Sons, Ltd.     

Measurement of glycine in healthy and tumorous brain by triple‐refocusing MRS at 3 T in vivo

Glycine (Gly) has been implicated in several neurological disorders, including malignant brain tumors. The precise measurement of Gly is challenging largely as a result of the spectral overlap with myo‐inositol (mI). We report a new triple‐refocusing sequence for the reliable co‐detection of Gly and mI at 3 T and for the evaluation of Gly in healthy and tumorous brain. The sequence parameters were optimized with density‐matrix simulations and phantom validation. With a total TE of 134 ms, the sequence gave complete suppression of the mI signal between 3.5 and 3.6 ppm and, consequently, well‐defined Gly (3.55 ppm) and mI (3.64 ppm) peaks. In vivo ¹H magnetic resonance spectroscopy (MRS) data were acquired from the gray matter (GM)‐dominant medial occipital and white matter (WM)‐dominant left parietal regions in six healthy subjects, and analyzed with LCModel using in‐house‐calculated basis spectra. Tissue segmentation was performed to obtain the GM and WM contents within the MRS voxels. Metabolites were quantified with reference to GM‐rich medial occipital total creatine at 8 mM. The Gly and mI concentrations were estimated to be 0.63 ± 0.05 and 8.6 ± 0.6 mM for the medial occipital and 0.34 ± 0.05 and 5.3 ± 0.8 mM for the left parietal regions, respectively. From linear regression of the metabolite estimates versus fractional GM content, the concentration ratios between pure GM and pure WM were estimated to be 2.6 and 2.1 for Gly and mI, respectively. Clinical application of the optimized sequence was performed in four subjects with brain tumor. The Gly levels in tumors were higher than those of healthy brain. Gly elevation was more extensive in a post‐contrast enhancing region than in a non‐enhancing region. The data indicate that the optimized triple‐refocusing sequence may provide reliable co‐detection of Gly and mI, and alterations of Gly in brain tumors can be precisely evaluated.     

Reproducibility and optimization of in vivo human diffusion‐weighted MRS of the corpus callosum at 3T and 7T

Diffusion‐weighted MRS (DWS) of brain metabolites enables the study of cell‐specific alterations in tissue microstructure by probing the diffusion of intracellular metabolites. In particular, the diffusion properties of neuronal N‐acetylaspartate (NAA), typically co‐measured with N‐acetylaspartyl glutamate (NAAG) (NAA + NAAG = tNAA), have been shown to be sensitive to intraneuronal/axonal damage in pathologies such as stroke and multiple sclerosis. Lacking, so far, are empirical assessments of the reproducibility of DWS measures across time and subjects, as well as a systematic investigation of the optimal acquisition parameters for DWS experiments, both of which are sorely needed for clinical applications of the method. In this study, we acquired comprehensive single‐volume DWS datasets of the human corpus callosum at 3T and 7T. We investigated the inter‐ and intra‐subject variability of empirical and modeled diffusion properties of tNAA [D_avg(tNAA) and D_model(tNAA), respectively]. Subsequently, we used a jackknife‐like resampling approach to explore the variance of these properties in partial data subsets reflecting different total scan durations. The coefficients of variation (C_V) and repeatability coefficients (C_R) for D_avg(tNAA) and D_model(tNAA) were calculated for both 3T and 7T, with overall lower variability in the 7T results. Although this work is limited to the estimation of the diffusion properties in the corpus callosum, we show that a careful choice of diffusion‐weighting conditions at both field strengths allows the accurate measurement of tNAA diffusion properties in clinically relevant experimental time. Based on the resampling results, we suggest optimized acquisition schemes of 13‐min duration at 3T and 10‐min duration at 7T, whilst retaining low variability (C_V ≈ 8%) for the tNAA diffusion measures. Power calculations for the estimation of D_model(tNAA) and D_avg(tNAA) based on the suggested schemes show that less than 21 subjects per group are sufficient for the detection of a 10% effect between two groups in case–control studies. Copyright © 2015 John Wiley & Sons, Ltd.     

Detection of lactate in the striatum without contamination of macromolecules by J‐difference editing MRS at 7 T

Lactate levels are measurable by MRS and are related to neural activity. Therefore, it is of interest to accurately measure lactate levels in the basal ganglia networks. If sufficiently stable, lactate measurements may be used to investigate alterations in dopaminergic signalling in the striatum, facilitating the detection and diagnosis of metabolic deficits. The aim of this study is to provide a J‐difference editing MRS technique for the selective editing of lactate only, thus allowing the detection of lactate without contamination of overlapping macromolecules. As a validation procedure, macromolecule nulling was combined with J‐difference editing, and this was compared with J‐difference editing with a new highly selective editing pulse. The use of a high‐field (7T) MR scanner enables the application of editing pulses with very narrow bandwidth, which are selective for lactate. We show that, despite the sensitivity to B₀ offsets, the use of a highly selective editing pulse is more efficient for the detection of lactate than the combination of a broad‐band editing pulse with macromolecule nulling. Although the signal‐to‐noise ratio of uncontaminated lactate detection in healthy subjects is relatively low, this article describes the test–retest performance of lactate detection in the striatum when using highly selective J‐difference editing MRS at 7 T. The coefficient of variation, σ_w and intraclass correlation coefficients for within‐ and between‐subject differences of lactate were determined. Lactate levels in the left and right striatum were determined twice in 10 healthy volunteers. Despite the fact that the test–retest performance of lactate detection is moderate with a coefficient of variation of about 20% for lactate, these values can be used for the design of new studies comparing, for example, patient populations with healthy controls. Copyright © 2015 John Wiley & Sons, Ltd.     

Progression of Alzheimer's disease and effect of scFv‐h3D6 immunotherapy in the 3xTg‐AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy

Alzheimer's disease (AD) is an incurable disease that affects most of the 47 million people estimated as living with dementia worldwide. The main histopathological hallmarks of AD are extracellular β‐amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. In recent years, Aβ‐immunotherapy has been revealed as a potential tool in AD treatment. One strategy consists of using single‐chain variable fragments (scFvs), which avoids the fragment crystallizable (Fc) effects that are supposed to trigger a microglial response, leading to microhemorrhages and vasogenic edemas, as evidenced in clinical trials with bapineuzumab. The scFv‐h3D6 generated by our research group derives from this monoclonal antibody, which targets the N‐terminal of the Aβ peptide and recognizes monomers, oligomers and fibrils. In this study, 3xTg‐AD mice were intraperitoneally and monthly treated with 100 μg of scFv‐h3D6 (a dose of ~3.3 mg/kg) or PBS, from 5 to 12 months of age (?mo), the age at which the mice were sacrificed and samples collected for histological and biochemical analyses. During treatments, four monitoring sessions using magnetic resonance imaging and spectroscopy (MRI/MRS) were performed at 5, 7, 9, and 12 months of age. MRI/MRS techniques are widely used in both human and mouse research, allowing to draw an in vivo picture of concrete aspects of the pathology in a non‐invasive manner and allowing to monitor its development across time. Compared with the genetic background, 3xTg‐AD mice presented a smaller volume in almost all cerebral regions and ages examined, an increase in both the intra and extracellular Aβ_1–42 at 12‐mo, and an inflammation process at this age, in both the hippocampus (IL‐6 and mIns) and cortex (IL‐6). In addition, treatment with scFv‐h3D6 partially recovered the values in brain volume, and Aβ, IL‐6, and mIns concentrations, among others, encouraging further studies with this antibody fragment.     

A comparative study of short‐ and long‐TE 1H MRS at 3 T for in vivo detection of 2‐hydroxyglutarate in brain tumors

2‐Hydroxyglutarate (2HG) is produced in gliomas with mutations of isocitrate dehydrogenase (IDH) 1 and 2. The ¹H resonances of the J‐coupled spins of 2HG are extensively overlapped with signals from other metabolites. Here, we report a comparative study at 3 T of the utility of the point‐resolved spectroscopy sequence with a standard short TE (35 ms) and a long TE (97 ms), which had been theoretically designed for the detection of the 2HG 2.25‐ppm resonance. The performance of the methods is evaluated using data from phantoms, seven healthy volunteers and 22 subjects with IDH‐mutated gliomas. The results indicate that TE = 97 ms provides higher detectability of 2HG than TE = 35 ms, and that this improved capability is gained when data are analyzed with basis spectra that include the effects of the volume localizing radiofrequency and gradient pulses. Copyright © 2013 John Wiley & Sons, Ltd.     

In vivo 1H MRS of WSU‐DLCL2 human non‐Hodgkin's lymphoma xenografts: response to rituximab and rituximab plus CHOP

In order to identify early ¹H MRS metabolic markers of response to rituximab immunotherapy and to rituximab plus CHOP (cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone) combination therapy, we performed an in vivo MRS investigation of a non‐Hodgkin's lymphoma (NHL) xenograft model. Human WSU‐DLCL2 NHL cells were subcutaneously implanted into flanks of female severe combined immunodeficient mice. When tumor volumes reached ～600 mm³, rituximab was administered for three weekly cycles at a dose of 25 mg/kg per cycle with or without CHOP. Before and after treatment, tumor lactate (Lac) and total choline (tCho) were detected using the selective multiple quantum coherence sequence and the stimulated echo acquisition mode sequence, respectively. Rituximab produced a small tumor growth delay (～5 days), whereas treatment with rituximab plus CHOP (RCHOP) led to ～20% tumor regression after three cycles of therapy. After one cycle of rituximab, the tCho/H₂O ratio had decreased significantly (5%, P = 0.003), whereas the Lac/H₂O ratio had not changed (P = 0.58). Both Lac/H₂O and tCho/H₂O had decreased after one cycle of RCHOP treatment (26%, P = 0.001; 10%, P = 0.016, respectively). After two cycles of RCHOP, Ki67 assay of histological tumor specimens indicated ～40% decrease in proliferation (P < 0.001) in the RCHOP‐treated tumors; no change was detected after treatment with rituximab alone. This study suggests that decreases in tCho/H₂O are more sensitive indices of response to rituximab, whereas decreases in Lac/H₂O are more sensitive to response to CHOP combination therapy. Copyright © 2008 John Wiley & Sons, Ltd.     

In vivo detection and automatic analysis of GABA in the mouse brain with MEGA‐PRESS at 9.4 T

The goals of this study were to develop an acquisition protocol and the analysis tools for Meshcher–Garwood point‐resolved spectroscopy (MEGA‐PRESS) in mouse brain at 9.4 T, to allow the in vivo detection of γ‐aminobutyric acid (GABA) and to examine whether isoflurane alters GABA levels in the thalamus during anesthesia. We implemented the MEGA‐PRESS sequence on a Bruker 94/20 system with ParaVision 6.0.1, and magnetic resonance spectra were acquired from nine male wild‐type C57BL/6 J mice at the thalamus. Four individual scans were obtained for each mouse in a 2‐h time course whilst the mouse was anesthetized with isoflurane. We developed an automated analysis program with improved correction for frequency and phase drift compared with the standard creatine (Cr) fitting‐based method and provided automatic quantification. During MEGA‐PRESS acquisition, a single voxel with a size of 5 × 3 × 3 mm³ was placed at the thalamus to evaluate GABA to Cr (GABA/Cr) ratios during anesthesia. Detection and quantitative analysis of thalamic GABA levels were successfully achieved. We noticed a significant decrease in GABA/Cr during the 2‐h anesthesia (by linear regression analysis: slope < 0, p < 0.0001). In summary, our findings demonstrate that MEGA‐PRESS is a feasible technique to measure in vivo GABA levels in the mouse brain at 9.4 T.     

Obstructive sleep apnea and risk of Parkinson's disease: a population‐based cohort study

Sleep disorders could be associated with neurodegenerative diseases. This study aimed to determine the risk of Parkinson's disease in patients with obstructive sleep apnea. The incident cases of newly diagnosed obstructive sleep apnea were identified between 2000 and 2009 from the medical claims database of National Health Institute of Taiwan. The risk of Parkinson's disease onset at least 1 year after the diagnosis of obstructive sleep apnea was measured during and up to 11 years of period, compared to that of age‐ and gender‐matched controls estimated in the same period. A total of 5864 patients with newly diagnosed obstructive sleep apnea and 23 269 subjects without obstructive sleep apnea were identified for data analysis. The study reported that the incidence of Parkinson's disease in the obstructive sleep apnea cohort was approximately two times higher than that in the control cohort (2.57 versus 1.32 per 1000 person‐years), with an adjusted hazard ratio of 1.84. Furthermore, the risk of Parkinson's disease was particularly greater for the obstructive sleep apnea with insomnia subgroup (adjusted hazard ratio = 1.97, 95% confidence interval = 1.44–2.69) than for the control cohort. The sex–age‐specific analysis further discovered that the most elevated risk of Parkinson's disease onset was noted in female obstructive sleep apnea patients aged 50–69 years (adjusted hazard ratio = 2.82). This population‐based study indicated that patients with obstructive sleep apnea, especially those who suffered from insomnia, are at an increased risk of Parkinson's disease onset.     

Unedited in vivo detection and quantification of γ‐aminobutyric acid in the occipital cortex using short‐TE MRS at 3 T

Short‐TE MRS has been proposed recently as a method for the in vivo detection and quantification of γ‐aminobutyric acid (GABA) in the human brain at 3 T. In this study, we investigated the accuracy and reproducibility of short‐TE MRS measurements of GABA at 3 T using both simulations and experiments. LCModel analysis was performed on a large number of simulated spectra with known metabolite input concentrations. Simulated spectra were generated using a range of spectral linewidths and signal‐to‐noise ratios to investigate the effect of varying experimental conditions, and analyses were performed using two different baseline models to investigate the effect of an inaccurate baseline model on GABA quantification. The results of these analyses indicated that, under experimental conditions corresponding to those typically observed in the occipital cortex, GABA concentration estimates are reproducible (mean reproducibility error, <20%), even when an incorrect baseline model is used. However, simulations indicate that the accuracy of GABA concentration estimates depends strongly on the experimental conditions (linewidth and signal‐to‐noise ratio). In addition to simulations, in vivo GABA measurements were performed using both spectral editing and short‐TE MRS in the occipital cortex of 14 healthy volunteers. Short‐TE MRS measurements of GABA exhibited a significant positive correlation with edited GABA measurements (R = 0.58, p < 0.05), suggesting that short‐TE measurements of GABA correspond well with measurements made using spectral editing techniques. Finally, within‐session reproducibility was assessed in the same 14 subjects using four consecutive short‐TE GABA measurements in the occipital cortex. Across all subjects, the average coefficient of variation of these four GABA measurements was 8.7 ± 4.9%. This study demonstrates that, under some experimental conditions, short‐TE MRS can be employed for the reproducible detection of GABA at 3 T, but that the technique should be used with caution, as the results are dependent on the experimental conditions. Copyright © 2013 John Wiley & Sons, Ltd.