In vivo magnetic resonance imaging characterization of bilateral structural changes in experimental Parkinson's disease: a T2 relaxometry study combined with longitudinal diffusion tensor imaging and manganese-enhanced magnetic resonance imaging in the 6-hydroxydopamine rat model

The neuropathological hallmark of Parkinson's disease is the loss of dopaminergic neurons in the pars compacta of the substantia nigra (SNc). The degenerative process starts unilaterally and spreads to the dopaminergic system of both hemispheres. However, the complete characterization of the nigra lesion and the subsequent changes in basal ganglia nuclei activity has not yet been achieved in vivo. The aim of this study was to characterize the time course of the nigral lesion in vivo, using longitudinal T2 relaxometry and diffusion tensor imaging, and the changes in basal ganglia nuclei activity, using manganese-enhanced magnetic resonance imaging, in 6-hydroxydopamine (6-OHDA)-lesioned rats. Our results showed that a unilateral SNc lesion induces bilateral alterations, as indicated by the enhancement of magnetic resonance imaging T2 relaxation times in both the ipsilateral and contralateral SNc. Moreover, axial and radial diffusivities demonstrated bilateral changes at 3 and 14 days after 6-OHDA injection in the pars reticulata of the substantia nigra and cortex, respectively, in comparison to the sham group, suggesting bilateral microstructural alterations in these regions. Unexpectedly, manganese-enhanced magnetic resonance imaging showed decreased axonal transport from the ipsilateral subthalamic nucleus to the ventral pallidum in 6-OHDA-lesioned animals compared with the sham group. These findings demonstrate, for the first time in vivo, the temporal pattern of bilateral alteration induced by the 6-OHDA model of Parkinson's disease, and indicate decreased axonal transport in the ipsilateral hemisphere.     

Regional alterations of brain microstructure in Parkinson's disease using diffusion tensor imaging

This study tested the hypothesis that diffusion tensor imaging can detect alteration in microscopic integrity of white matter and basal ganglia regions known to be involved in Parkinson's disease (PD) pathology. It was also hypothesized that there is an association between diffusion abnormality and PD severity and subtype. Diffusion tensor imaging at 4 Tesla was obtained in 12 PD and 20 control subjects, and measures of fractional anisotropy and mean diffusivity were evaluated using both region‐of‐interest and voxel‐based methods. Movement deficits and subtypes in PD subjects were assessed using the Motor Subscale (Part III) of the Unified Parkinson's Disease Rating Scale. Reduced fractional anisotropy (P < .05, corrected) was found in PD subjects in regions related to the precentral gyrus, substantia nigra, putamen, posterior striatum, frontal lobe, and the supplementary motor areas. Reduced fractional anisotropy in the substantia nigra correlated (P < .05, corrected) with the increased rating scale motor scores. Significant spatial correlations between fractional anisotropy alterations in the putamen and other PD‐affected regions were also found in the context of PD subtypes index analysis. Our data suggest that microstructural alterations detected with diffusion tensor might serve as a potential biomarker for PD. © 2011 Movement Disorder Society     

Functional imaging of subthalamic nucleus deep brain stimulation in Parkinson's disease

Deep brain stimulation of the subthalamic nucleus is an accepted treatment for the motor complications of Parkinson's disease. The therapeutic mechanism of action remains incompletely understood. Although the results of deep brain stimulation are similar to the results that can be obtained by lesional surgery, accumulating evidence from functional imaging and clinical neurophysiology suggests that the effects of subthalamic nucleus‐deep brain stimulation are not simply the result of inhibition of subthalamic nucleus activity. Positron emission tomography/single‐photon emission computed tomography has consistently demonstrated changes in cortical activation in response to subthalamic nucleus‐deep brain stimulation. However, the technique has limited spatial and temporal resolution, and therefore the changes in activity of subcortical projection sites of the subthalamic nucleus (such as the globus pallidus, substantia nigra, and thalamus) are not as clear. Clarifying whether clinically relevant effects from subthalamic nucleus‐deep brain stimulation in humans are mediated through inhibition or excitation of orthodromic or antidromic pathways (or both) would contribute to our understanding of the precise mechanism of action of deep brain stimulation and may allow improvements in safety and efficacy of the technique. In this review we discuss the published evidence from functional imaging studies of patients with subthalamic nucleus‐deep brain stimulation to date, together with how these data inform the mechanism of action of deep brain stimulation. © 2011 Movement Disorder Society     

In vivo measurement of blood oxygen saturation using magnetic resonance imaging: A direct validation of the blood oxygen level-dependent concept in functional brain imaging

A novel noninvasive magnetic resonance imaging (MRI) method was developed to determine in vivo blood oxygen saturation and its changes during motor cortex activation in small cerebral veins. Specifically, based on susceptibility measurements in the resting states, pial veins were found to have a mean oxygen saturation of Y_rest = 0.544 ± 0.029 averaged over 14 vessels in 5 volunteers. During activation, susceptibility measurements revealed an oxygen saturation change of ΔY_susc = 0.14 ± 0.02. Independent evaluation from blood flow velocity measurements yielded a value of ΔY_flow = 0.14 ± 0.04 for this change. These results validate the blood oxygenation level-dependent (BOLD) model in functional MRI (fMRI). Hum. Brain Mapping 5:341–346, 1997. © 1997 Wiley-Liss, Inc.     

Magnetic resonance imaging markers for early diagnosis of Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by selective and progressive degeneration, as well as loss of dopaminergic neurons in the substantia nigra. In PD, approximately 60-70% of nigrostriatal neurons are degenerated and 80% of content of the striatal dopamine is reduced before the diagnosis can be established according to widely accepted clinical diagnostic criteria. This condition describes a stage of disease called "prodromal", where non-motor symptoms, such as olfactory dysfunction, constipation, rapid eye movement behaviour disorder, depression, precede motor sign of PD. Detection of prodromal phase of PD is becoming an important goal for determining the prognosis and choosing a suitable treatment strategy. In this review, we present some non-invasive instrumental approaches that could be useful to identify patients in the prodromal phase of PD or in an early clinical phase, when the first motor symptoms begin to be apparent. Conventional magnetic resonance imaging (MRI) and advanced MRI techniques, such as magnetic resonance spectroscopy imaging, diffusion-weighted and diffusion tensor imaging and functional MRI, are useful to differentiate early PD with initial motor symptoms from atypical parkinsonian disorders, thus, making easier early diagnosis. Functional MRI and diffusion tensor imaging techniques can show abnormalities in the olfactory system in prodromal PD.     

An experimental brainstem tumor model using in vivo bioluminescence imaging in rat

Purpose  Currently, there is no conclusive treatment for brainstem tumor. To facilitate the development of new treatments, it is essential to establish predictive preclinical in vivo models in which therapeutic modalities can be evaluated. Although a few rodent models have been reported, there is no novel approach that can monitor tumor response qualitatively and quantitatively. Materials and methods  Bioluminescence imaging was used to characterize a rat brainstem tumor model. In this model, 9L gliosarcoma cells, transduced with an onco-retroviral vector containing the luciferase coding sequence, were inoculated into Fisher 344 rats. Result  Histopathological assessment showed successful cell implantation into the brainstem. There was a strong correlation between pathological tumor volume and luminescence strength. Longitudinal quantitative responses of the tumor after application of a therapeutic agent were also demonstrated. Conclusion  This study demonstrates a robust rodent model with the ability to monitor brainstem tumor growth and response to chemotherapeutic agents.     

Magnetic resonance imaging findings of shoulders in Parkinson's disease

The aim of this study is to evaluate shoulder disturbances in Parkinson's disease (PD) patients using magnetic resonance imaging (MRI) which is the best tool in the demonstration of complex shoulder pathologies; and to determine probable relations between shoulder pathologies and PD clinical features. Twenty‐eight PD patients with a total of 56 shoulders were used as the study group while 13 age‐matched cases with 26 shoulders were used as the control group (CG) in the study. Both patients with PD and the CG underwent shoulder MRI. The Hoehn and Yahr (H&Y) disability scale and Unified Parkinson's Disease Rated Scale (UPDRS) were used to determine the severity of the disease. Our results showed that patients with full‐thickness supraspinatus (SSP) tear have statistically significant higher UPDRS (P = 0.012), tremor (P = 0.023), rigidity (P = 0.023), and total (P = 0.002) scores. Mild group patients (P = 0.045) showed significantly higher frequency resting tremor and subcoracoid effusion than those of severe group patients (P = 0.002). Subcoracoid effusion was observed in patients with significantly higher UPDRS (P = 0.045) and rigidity (P = 0.022) scores. When the resting tremor and subcoracoid effusion groups were compared according to the severity of the resting tremor but not according to the H&Y, higher frequency of full‐thickness tear in SSP tendon was detected in the group of resting tremor (P = 0.053). Longer duration of disease was also observed in patients with full‐thickness SSP tear (P = 0.029) and acromioclavicular joint changes (P = 0.018). Higher UPDRS, tremor, rigidity and total scores and longer PD duration appear as the predisposing factors for the development of shoulder disturbances in PD in this study. © 2010 Movement Disorder Society     

Blood–brain barrier opening with focused ultrasound in experimental models of Parkinson's disease

Parkinson's disease has many symptomatic treatments, but there is no neuroprotective therapy currently available. The evolution of this disease is inexorably progressive, and halting or stopping the neurodegenerative process is a major unmet need. Parkinson's disease motor features at onset are typically limited to 1 body segment, that is, focal signs, and the nigrostriatal degeneration is highly asymmetrical and mainly present in the caudal putamen. Thus, clinically and neurobiologically the process is fairly limited early in its evolution. Tentatively, this would allow the possibility of intervening to halt neurodegeneration at the most vulnerable site. The recent use of new technologies such as focused ultrasound provides interesting prospects. In particular, the possibility of transiently opening the blood–brain barrier to facilitate penetrance of putative neuroprotective agents is a highly attractive approach that could be readily applied to Parkinson's disease. However, because there are currently effective treatments available (ie, dopaminergic pharmacological therapy), more experimental evidence is needed to construct a feasible and practical therapeutic approach to be tested early in the evolution of Parkinson's disease patients. In this review, we provide the current evidence for the application of blood–brain barrier opening in experimental models of Parkinson's disease and discuss its potential clinical applicability. © 2019 International Parkinson and Movement Disorder Society     

On the role of quantitative brain imaging in the differential diagnosis of speech disorders

We present the case of a 71-year-old woman with an 11-year history of slowly progressive decline of motor speech. Normal clinical investigations including routine magnetic resonance imaging (MRI) at 7, 8 and 10 years after the onset of speech dysfunction led to the suggestion of a psychogenic disorder. Extensive clinical, neuropsychological and neuroimaging investigations including 18F-desoxyglucose-positron emission tomography (PET), quantitative MRI and MR spectroscopy were performed to look for subtle brain pathology. Quantitative assessment of 3D-MRI, F-desoxyglucose-PET and magnetic resonance spectroscopy all demonstrated clear evidence of multifocal frontotemporal brain pathology that had not been picked up on routine MRI investigations on previous admissions. This is the longest benign history of slowly progressive anarthria reported so far. It demonstrates a possible role of quantitative neuroimaging techniques in the diagnosis of complex neuropsychiatric disorders.     

Reduced cerebral blood flow in an α-synuclein transgenic mouse model of Parkinson’s disease

There is increasing evidence that widespread cortical cerebral blood flow deficits occur early in the course of Parkinson’s disease. Although cerebral blood flow measurement has been suggested as a potential biomarker for early diagnosis of Parkinson’s disease, as well as a means for tracking response to treatment, the relationship of cerebral blood flow to α-synucleinopathy, a major pathological hallmark of Parkinson’s disease, remains unclear. Therefore, we performed arterial spin-labeling magnetic resonance imaging and diffusion tensor imaging on transgenic mice overexpressing human wild-type α-synuclein and age-matched controls to measure cerebral blood flow and degenerative changes. As reported for early-stage Parkinson’s disease, α-synuclein mice exhibited a significant reduction in cortical cerebral blood flow, which was accompanied by motor coordination deficits and olfactory dysfunction. Although no overt degenerative changes were apparent in diffusion tensor imaging images, magnetic resonance imaging volumetric analysis revealed a significant reduction in olfactory bulb volume, similar to that seen in Parkinson’s disease patients. Our data, representing the first report of cerebral blood flow deficit in an animal model of Parkinson’s disease, suggest a causative role for α-synucleinopathy in cerebral blood flow deficits in Parkinson’s disease. Thus, α-synuclein transgenic mice comprise a promising model to study Parkinson’s disease-related mechanisms of cerebral blood flow deficits and to investigate further its utility as a potential biomarker for Parkinson’s disease.     

MR imaging of the brain in patients with hepatic form of Wilson''s disease

The aim of this study was to detect the sites and frequency of possible lesions by brain magnetic resonance imaging (MRI; 1,5T) in a group of 16 neurologically asymptomatic patients with hepatic form of Wilson's disease (WD; seven untreated and nine under treatment). Abnormal MR findings of the brain were found in 75% of patients. Lesions in brain parenchyma were detected in all untreated, drug-naive patients and in 44% of treated patients. Abnormal signal in globus pallidus, putamen, and caudate nucleus was revealed in 86, 71 and 71% of treated and in 33, 33 and 22% of untreated patients, respectively. In five of eight patients with putaminal pathology (62.5%) and in four of seven patients with caudate nuclei involvement (57%), only proton density 2-weighted sequence (PDW) exhibited sensitivity for lesion detection, with both T1W and long echo T2W sequences being insensitive. This superiority of PDW sequence was even more pronounced in the group of untreated patients in whom 80% of putaminal pathology was visible exclusively on this sequence. The lower frequency of lesions in the group of treated in comparison with untreated patients indicated that they might be reversible in the course of chronic chelating therapy.     

The bidirectional association between reduced cerebral blood flow and brain atrophy in the general population

The question remains whether reduced cerebral blood flow (CBF) leads to brain atrophy or vice versa. We studied the longitudinal relation between CBF and brain volume in a community-dwelling population. In the Rotterdam Study, 3011 participants (mean age 59.6 years (s.d. 8.0)) underwent repeat brain magnetic resonance imaging to quantify brain volume and CBF at two time points. Adjusted linear regression models were used to investigate the bidirectional relation between CBF and brain volume. We found that smaller brain volume at baseline was associated with a steeper decrease in CBF in the whole population (standardized change per s.d. increase of total brain volume (TBV)=0.296 (95% confidence interval (CI) 0.200; 0.393)). Only in persons aged ⩾65 years, a lower CBF at baseline was associated with steeper decline of TBV (standardized change per s.d. increase of CBF=0.003 (95% CI −0.004; 0.010) in the whole population and 0.020 (95% CI 0.004; 0.036) in those aged ⩾65 years of age). Our results indicate that brain atrophy causes CBF to decrease over time, rather than vice versa. Only in persons aged >65 years of age did we find lower CBF to also relate to brain atrophy.     

T1‐Weighted MRI shows stage‐dependent substantia nigra signal loss in Parkinson's disease

Depigmentation of the substantia nigra is a conspicuous pathological feature of Parkinson's disease and related to a loss of neuromelanin. Similar to melanin, neuromelanin has paramagnetic properties resulting in signal increase on specific T1‐weighted magnetic resonance imaging. The aim of this study was to assess signal changes in the substantia nigra in patients with Parkinson's disease using an optimized neuromelanin‐sensitive T1 scan. Ten patients with Parkinson's disease and 12 matched controls underwent high‐resolution T1‐weighted magnetic resonance imaging with magnetization transfer effect at 3T. The size and signal intensity of the substantia nigra pars compacta were determined as the number of pixels with signal intensity higher than background signal intensity + 3 standard deviations and regional contrast ratio. Patients were subclassified as early stage (n = 6) and late stage (n = 4) using the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr Parkinson's disease staging scale. The T1 hyperintense area in the substantia nigra was substantially smaller in patients compared with controls (?60%, P < .01), and contrast was reduced (?3%, P < .05). Size reduction was even more pronounced in more advanced disease (?78%) than in early‐stage disease (?47%). We present preliminary findings using a modified T1‐weighted magnetic resonance imaging technique showing stage‐dependent substantia nigra signal reduction in Parkinson's disease as a putative marker of neuromelanin loss. Our data suggest that reduction in the size of neuromelanin‐rich substantia nigra correlates well with postmortem observations of dopaminergic neuron loss. Further validation of our results could potentially lead to development of a new biomarker of disease progression in Parkinson's disease. © 2011 Movement Disorder Society     

脑功能磁共振成像研究进展

主要综述fMRI产生的历史、成像原理、成像技术和方法、已经取得的成绩以及将来研究发展的方向等。fMRI产生技术广泛应用的20世纪90年代,主要受快速成像技术的影响,从有创走向无创,从而受到神经、认知和心理科学领域的极大关注。fMRI原理是根据神经元兴奋后局部氧耗与血流增幅不一致,而BOLD效应机制成像,间接显示神经元活动。成像主要采用平面回波成像（EPI）和快速小角度激发（FLASH）技术、二者在时间和空间分辨率上各有优劣。最后几年来,fMRI技术对脑功能的研究已取得了巨大的成绩,估计将在这一领域继续拥有非常重要的地位。将来fMRI可能主要在BOLD效应的生理过程、临床应用以及高场磁体的应用等领域进一步展开。     

Ventricular dilatation and brain atrophy in patients with Parkinson's disease with incipient dementia

Age‐related ventricular enlargement is accelerated in Alzheimer's disease, but its relationship to cognitive decline in Parkinson's disease is less clear, even though dementia is common in Parkinson's disease. Our goals were to determine if greater enlargement of the ventricles and gray or white matter atrophy occurred in Parkinson's disease patients developing cognitive decline. Older nondemented patients with Parkinson's disease (33) and age‐ and sex‐matched controls (39) were recruited and prospectively assessed for the development of significant cognitive decline over 36 months. Magnetic resonance imaging was obtained every 18 months, and ventricular volume and total brain gray and white matter volumes were measured using reliable segmentation of T1‐weighted volumetric scans. Subjects with incidental intracranial abnormalities, an atypical course, and stroke as well as dropouts were excluded from a cohort of 52 patients and 50 controls. Among 33 patients and 39 controls, 10 patients and 3 controls developed significant cognitive impairment or dementia. Ventricular change and Parkinson's disease status were significantly associated with dementia. Ventricular change was significantly correlated with change in Mini‐Mental Status Examination in the Parkinson's disease with dementia group (r = 0.87, P = .001). Gray matter atrophy was greater in Parkinson's disease with dementia, with similar change over time in both Parkinson's disease and Parkinson's disease with dementia. White matter volumes were not significantly different between Parkinson's disease and Parkinson's disease with dementia; however, the decrease over time might be greater in Parkinson's disease with dementia. Ventricular dilatation occurs early in the course of significant cognitive decline in patients with Parkinson's disease, possibly reflecting both cortical gray and white matter loss. © 2011 Movement Disorder Society     

Correlation between iron deposition and Alzheimer's disease In vivo preliminary quantitative study with susceptibility-weighted imaging

BACKGROUND: Studies have demonstrated iron deposition in Alzheimer's disease (AD) patients. Therefore, quantitative measurements and tracing of iron deposition are important for early detection and treatment.OBJECTIVE: To quantitatively measure iron deposition in the brain and evaluate the relationship between iron deposition and AD using magnetic susceptibility-weighted imaging. DESIGN, TIME AND SETTING: A case-control study was performed at the Department of Radiology, Huashan Hospital of Fudan University from February to July 2008. PARTICIPANTS: A total of 20 AD patients, comprising 11 males and 9 females, with a mean age of 72.5 years (range, 51-80 years), and 20 healthy volunteers, comprising 10 males and 10 females, with a mean age of 69.9 years (range, 55-78 years), were selected. AD was diagnosed according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association criteria.METHODS: Sagittal T2-weighted images were acquired to locate precise positions of the anterior and posterior commissures. The susceptibility-weighted magnetic resonance images were parallel to the anterior-posterior commissural line through the use of a three-dimensional gradient-echo sequence. All participants underwent measurement of corrected phase (CP) value and Mini-Mental State Examination. Pearson correlation coefficients were used to assess the association between CP values and Mini-Mental State Examination results.MAIN OUTCOME MEASURES: CP values of regions of interest in the hippocampal regions were measured on CP images.RESULTS: CP values were significantly reduced in bilateral hippocampal regions of AD patients compared with normal controls (P＜0.01), but there were no significant differences between left and right CP values (P＞0.05). The hippocampal mean CP value positively correlated with the Mini-Mental State Examination score in AD patients and normal controls (r= 0.57, P＜0.01). CONCLUSION: Susceptibility-weighted imaging can be used to measure CP values to determine iron deposition in the brains of AD patients and could serve as a useful diagnostic tool for AD.     

Distinct functional and macrostructural brain changes in Parkinson's disease and multiple system atrophy

Parkinson's disease (PD) and the parkinsonian variant of multiple system atrophy (MSAp) are neurodegenerative disorders that can be difficult to differentiate clinically. This study provides the first characterization of the patterns of task‐related functional magnetic resonance imaging (fMRI) changes across the whole brain in MSAp. We used fMRI during a precision grip force task and also performed voxel‐based morphometry (VBM) on T₁‐weighted images in MSAp patients, PD patients, and healthy controls. All groups were matched on age, and the patient groups had comparable motor symptom durations and severities. There were three main findings. First, MSAp and PD had reduced fMRI activation in motor control areas, including the basal ganglia, thalamus, insula, primary sensorimotor and prefrontal cortices, and cerebellum compared with controls. Second, there were no activation differences among the disease groups in the basal ganglia, thalamus, insula, or primary sensorimotor cortices, but PD had more extensive activation deficits throughout the cerebrum compared with MSAp and controls. Third, VBM revealed reduced volume in the basal ganglia, middle and inferior cerebellar peduncles, pons, and throughout the cerebrum in MSAp compared with controls and PD, and additionally throughout the cerebellar cortex and vermis in MSAp compared with controls. Collectively, these results provide the first evidence that fMRI activation is abnormal in the basal ganglia, cerebellum, and cerebrum in MSAp, and that a key distinguishing feature between MSAp and PD is the extensive and widespread volume loss throughout the brain in MSAp. Hum Brain Mapp 36:1165–1179, 2015. © 2014 Wiley Periodicals, Inc.