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Changes in brain functional connectivity patterns are driven by an individual lesion in MS: a resting-state fMRI study
Diffuse inflammation in multiple sclerosis (MS) extends beyond focal lesion sites, affecting interconnected regions; however, little is known about the impact of an individual lesion affecting major white matter (WM) pathways on brain functional connectivity (FC). Here, we longitudinally assessed the effects of acute and chronic lesions on FC in relapsing-remitting MS (RRMS) patients using resting-state fMRI. 45 MRI data sets from 9 RRMS patients were recorded using 3T MR scanner over 5 time points at 8 week intervals. Patients were divided into two groups based on the presence (n = 5; MS+) and absence (n = 4; MS-) of a lesion at a predilection site for MS. While FC levels were found not to fluctuate significantly in the overall patient group, the MS+ patient group showed increased FC in the contralateral cuneus and precuneus and in the ipsilateral precuneus (p < 0.01, corrected). This can be interpreted as the recruitment of intact cortical regions to compensate for tissue damage. During the study, one patient developed an acute WM lesion in the left posterior periventricular space. A marked increase in FC in the right pre-, post-central gyrus, right superior frontal gyrus, the left cuneus, the vermis and the posterior and anterior lobes of the cerebellum was noted following the clinical relapse, which gradually decreased in subsequent follow-ups, suggesting short-term functional reorganization during the acute phase. This strongly suggests that the lesion-related network changes observed in patients with chronic lesions occur as a result of reorganization processes following the initial appearance of an acute lesion.
Changes and variability of proton density and T1 relaxation times in early multiple sclerosis: MRI markers of neuronal damage in the cerebral cortex
Objectives: Proton density (PD) and T1 relaxation time are promising quantitative MRI (qMRI) markers of neuronal damage in multiple sclerosis (MS). However, it is unknown whether cortical differences of these parameters between patients and controls exist in the early stages of disease. This study investigates cortical T1 and PD in early MS stages, hypothesizing that these are altered and display a high spatial variability. Methods: Quantitative T1 and PD mapping was performed on 11 patients with clinically isolated syndrome (CIS)/early MS in remission and 11 healthy controls. The normal appearing cortical gray matter was extracted, lobar regions were identified, and mean values and standard deviations of both parameters were calculated within each region. Results: Increased PD was detected in MS/CIS patients in the cerebral cortex as a whole and all subregions, indicating an increase of water content. Increase of PD variability reached significance in the whole cortex and in the frontal and parietal regions. Longer T1 relaxation times and increased variability were found in the cerebral cortex in all regions studied, indicating a change of microstructural tissue composition that is spatially heterogeneous. Conclusions: The data show spatially heterogeneous cortical involvement in early MS is reflected in T1 and PD qMRI. Key Points: • Cortical involvement in early MS is reflected in T1/PD quantitative MRI. • The changes are spatially heterogeneous. • Cortical damage goes beyond increased water content.
Assessment of cortical damage in early multiple sclerosis with quantitative T2 relaxometry
T2 relaxation time is a quantitative MRI in vivo surrogate of cerebral tissue damage in multiple sclerosis (MS) patients. Cortical T2 prolongation is a known feature in later disease stages, but has not been demonstrated in the cortical normal appearing gray matter (NAGM) in early MS. This study centers on the quantitative evaluation of the tissue parameter T2 in cortical NAGM in a collective of early MS and clinically isolated syndrome (CIS) patients, hypothesizing that T2 prolongation is already present at early disease stages and variable over space, in line with global and focal inflammatory processes in MS. Additionally, magnetization transfer ratio (MTR) mapping was performed for further characterization of the expected cortical T2 alteration. Quantitative T2 and MTR maps were acquired from 12 patients with CIS and early MS, and 12 matched healthy controls. The lesion-free part of the cortical volume was identified, and the mean T2 and MTR values and their standard deviations within the cortical volume were determined. For evaluation of spatial specificity, cortical lobar subregions were tested separately for differences of mean T2 and T2 standard deviation. We detected significantly prolonged T2 in cortical NAGM in patients. T2 prolongation was found across the whole cerebral cortex and in all individual lobar subregions. Significantly higher standard deviations across the respective region of interest were found for the whole cerebral cortex and all subregions, suggesting the occurrence of spatially inhomogeneous cortical damage in all regions studied. A trend was observed for MTR reduction and increased MTR variability across the whole cortex in the MS group, suggesting demyelination. In conclusion, our results suggest that cortical damage in early MS is evidenced by spatially inhomogeneous T2 prolongation which goes beyond demyelination. Iron deposition, which is known to decrease T2, seems less prominent.
Quantitative T1 and proton density mapping with direct calculation of radiofrequency coil transmit and receive profiles from two-point variable flip angle data
Quantitative T1 mapping of brain tissue is frequently based on the variable flip angle (VFA) method, acquiring spoiled gradient echo (GE) datasets at different excitation angles. However, accurate T1 calculation requires a knowledge of the sensitivity profile B1 of the radiofrequency (RF) transmit coil. For an additional derivation of proton density (PD) maps, the receive coil sensitivity profile (RP) must also be known. Mapping of B1 and RP increases the experiment duration, which may be critical when investigating patients. In this work, a method is presented for the direct calculation of B1 and RP from VFA data. Thus, quantitative maps of T1, PD, B1 and RP can be obtained from only two spoiled GE datasets. The method is based on: (1) the exploitation of the linear relationship between 1/PD and 1/T1 in brain tissue and (2) the assumption of smoothly varying B1 and RP, so that a large number of data points can be fitted across small volume elements where B1 and RP are approximately constant. The method is tested and optimized on healthy subjects.
Meningeal disorders
Meningeal disorders of the spine form a heterogenous group of diseases, affecting the spinal cord and its nerve roots through their intimate contact. Meningeal disease can, at times, present with back pain only. However, neurological symptoms are the more common manifestation leading to diagnosis, be it through compression of the spinal cord or of the spinal nerves. MRI is the imaging modality of choice when meningeal disease of the spine is suspected. Wherever possible, imaging studies should precede diagnostic lumbar puncture, because contrast enhancement of the dural sac can occur subsequent to lumbar puncture. If imaging is performed after lumbar puncture, it may be impossible to distinguish between enhancement through meningeal disease and transient changes subsequent to opening of the dural space.
Gray matter diseases of the spinal cord
Gray matter diseases of the spinal cord cover a heterogenous group of inherited disorders, infectious and sporadic diseases. Typical examples include the spinal muscular atrophies, poliomyelitis, and motor neuron diseases. Clinical symptoms, age at onset, rate of progression, family history, and electrophysiological findings will help make the diagnosis.
Diseases of the spinal cord: Novel imaging, diagnosis and treatment
This book documents current knowledge on the mechanisms involved in sports injuries to the shoulder and elbow, reviews essential physical examinations, and explains the role of diagnostic imaging. Above all, it describes in detail the treatment modalities that are appropriate to the injuries encountered in throwing and overhead athletes, including chronic repetitive and acute traumatic injuries. Both conservative and surgical treatments are covered; the author's own preferred operative techniques are identified and explained, and helpful treatment algorithms offer guidance in selecting an approach fitting to the circumstances. In addition, the inclusion of instructive case reviews will assist readers in achieving a full understanding of the implementation of treatment protocols. Methods of rehabilitation are also described with the aid of demonstration videos, and advice is provided on appropriate timing. The book will be invaluable for all professionals who deal with sports injuries of the shoulder and elbow, including surgeons, physiotherapists, other medical practitioners, and trainers.?Spinal cord imaging has significantly benefited from a variety of new MR imaging methods. Recent decades have also witnessed fundamental progress in understanding of the pathophysiology of spinal cord diseases, treatment options, neurosurgical procedures, and endovascular treatments. This textbook provides an interdisciplinary overview of the new imaging modalities, identifies clues for MR imaging diagnosis and differential diagnosis and describes the anatomical background required to understand spinal cord diseases. Important neurological symptoms are highlighted, and modern treatment options for different diseases are fully explained and discussed. High-quality illustrations, including numerous images, are provided for all important spinal cord diseases, documenting relevant anatomical details, special MR imaging methods, differential diagnoses and possible treatment procedures.
White matter damage is related to ataxia severity in SCA3
Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar ataxia in Europe, the US and Japan, leading to disability and death through motor complications. Although the affected protein ataxin-3 is found ubiquitously in the brain, grey matter atrophy is predominant in the cerebellum and the brainstem. White matter pathology is generally less severe and thought to occur in the brainstem, spinal cord, and cerebellar white matter. Here, we investigated both grey and white matter pathology in a group of 12 SCA3 patients and matched controls. We used voxel-based morphometry for analysis of tissue loss, and tract-based spatial statistics (TBSS) on diffusion magnetic resonance imaging to investigate microstructural pathology. We analysed correlations between microstructural properties of the brain and ataxia severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) score. SCA3 patients exhibited significant loss of both grey and white matter in the cerebellar hemispheres, brainstem including pons and in lateral thalamus. On between-group analysis, TBSS detected widespread microstructural white matter pathology in the cerebellum, brainstem, and bilaterally in thalamus and the cerebral hemispheres. Furthermore, fractional anisotropy in a white matter network comprising frontal, thalamic, brainstem and left cerebellar white matter strongly and negatively correlated with SARA ataxia scores. Tractography identified the thalamic white matter thus implicated as belonging to ventrolateral thalamus. Disruption of white matter integrity in patients suffering from SCA3 is more widespread than previously thought. Moreover, our data provide evidence that microstructural white matter changes in SCA3 are strongly related to the clinical severity of ataxia symptoms. © Springer-Verlag 2013.
The value of putaminal diffusion imaging versus 18-fluorodeoxyglucose positron emission tomography for the differential diagnosis of the Parkinson variant of multiple system atrophy
Differentiating the Parkinson variant of multiple system atrophy (MSA-P) from idiopathic Parkinson's disease (PD) and other forms of atypical parkinsonism can be difficult because symptoms overlap considerably. 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) is a powerful imaging technique that can assist in the diagnosis of MSA-P via detection of putaminal and cerebellar hypometabolism. Recent studies suggest that diffusion-weighted imaging (DWI) might be of similar diagnostic value, as it can detect microstructural damage in the putamen by means of an increased mean diffusivity (MD). The aim of this study was a direct comparison of DWI and FDG-PET by using both methods on the same subject cohort. To this end, combined DWI and FDG-PET were employed in patients with MSA-P (n=11), PD (n=13), progressive supranuclear palsy (n=8), and in 6 control subjects. MD values and FDG uptake ratios were derived from volumetric parcellations of the putamen and subjected to further analysis of covariance (ANCOVA) and receiver operating characteristics analyses. MSA-P was found to be associated with an increased posterior putaminal MD (P<0.001 in all subgroup comparisons) that correlated strongly with local reductions in FDG uptake (r=-0.85, P=0.002). DWI discriminated patients with MSA-P from other subgroups nearly as accurately as FDG-PET (area under the curve=0.89 vs 0.95, P=0.27 [pooled data]). Our data suggest a close association between the amount of putaminal microstructural damage and a reduced energy metabolism in patients with MSA-P. The clinical use of DWI for the differential diagnosis of MSA-P is encouraged. © 2013 International Parkinson and Movement Disorder Society.
Diffusion Imaging in Tremor
In recent years, diffusion-weighted magnetic resonance imaging (DWI) has complemented established imaging techniques for studying the human brain in health and disease. DWI is an MR technique that probes the motion of free water undergoing spontaneous diffusion in the living tissue. Unlike conventional, structural MRI, this method provides insights into the microscopic composition, integrity, and orientation of structures in the human brain (Le Bihan 2003).
The Bioenergetic Status Relates to Dopamine Neuron Loss in Familial PD with PINK1 Mutations
Mutations in the PINK1 gene cause autosomal recessive familial Parkinson's disease (PD). The gene encodes a mitochondrial protein kinase that plays an important role in maintaining mitochondrial function and integrity. However, the pathophysiological link between mutation-related bioenergetic deficits and the degenerative process in dopaminergic neurons remains to be elucidated. We performed phosphorous (31P) and proton (1H) 3-T magnetic resonance spectroscopic imaging (MRSI) in 11 members of a German family with hereditary PD due to PINK1 mutations (PARK6) compared to 23 age-matched controls. All family members had prior 18-Fluorodopa (FDOPA) positron emission tomography (PET). The striatal FDOPA uptake was correlated with quantified metabolic brain mapping in MRSI. At group level, the heterozygous PINK1 mutation carriers did not show any MRSI abnormalities relative to controls. In contrast, homozygous individuals with manifest PD had putaminal GPC, PCr, HEP and β-ATP levels well above the 2SD range of controls. Across all subjects, the FDOPA Ki values correlated positively with MI (r = 0.879, p<0.001) and inversely with β-ATP (r = -0.784, p = 0.008) and GPC concentrations (r = -0.651, p = 0.030) in the putamen. Our combined imaging data suggest that the dopaminergic deficit in this family with PD due to PINK1 mutations relates to osmolyte dysregulation, while the delivery of high energy phosphates was preserved. Our results corroborate the hypothesis that PINK1 mutations result in reduced neuronal survival, most likely due to impaired cellular stress resistance. © 2012 Hilker et al.
MR volumetric changes after diagnostic CSF removal in normal pressure hydrocephalus
Although diagnostic CSF removal in patients with suspected normal pressure hydrocephalus (NPH) is performed frequently, its impact on changes of the global brain volume and volume of the ventricles has not been studied in detail. We examined 20 patients with clinical and radiological signs of NPH. These received MRI prior to and immediately after diagnostic CSF removal, either via lumbar puncture (TAP, n = 10) or via external lumbar drainage (ELD, n = 10). Changes in global brain volume were assessed using SIENA, a tool from the FSL software library. Additionally, we determined the change of the lateral ventricles' volume by manual segmentation. Furthermore, we recorded systematic clinical assessments of the key features of NPH. The median volume of CSF removed was 35 ml in TAP patients and 406 ml in ELD patients. Changes in global brain volume were found in both patient groups. Brain volume change was significantly larger in ELD patients than in TAP patients (p = 0.022), and correlated with the volume of CSF removal (r = 0.628, p = 0.004). Brain volume expansion was most pronounced adjacent to the lateral ventricles, but also detectable in the temporal and frontal regions. The median ventricular volume decreased after CSF removal. Ventricular volume reduction was more pronounced in ELD patients than in TAP patients. This study quantifies for the first time immediate volumetric changes of global brain tissue and of ventricles after diagnostic CSF removal in NPH patients. In particular, we report evidence that CSF removal results in a change of the brain volume rather than only a change of the brain's shape. © Springer-Verlag 2012.
Presynaptic Dopaminergic Imaging Characterizes Patients with REM Sleep Behavior Disorder Due to Synucleinopathy.
OBJECTIVE: To apply a machine learning analysis to clinical and presynaptic dopaminergic imaging data of patients with rapid eye movement (REM) sleep behavior disorder (RBD) to predict the development of Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: In this multicenter study of the International RBD study group, 173 patients (mean age 70.5 ± 6.3 years, 70.5% males) with polysomnography-confirmed RBD who eventually phenoconverted to overt alpha-synucleinopathy (RBD due to synucleinopathy) were enrolled, and underwent baseline presynaptic dopaminergic imaging and clinical assessment, including motor, cognitive, olfaction, and constipation evaluation. For comparison, 232 RBD non-phenoconvertor patients (67.6 ± 7.1 years, 78.4% males) and 160 controls (68.2 ± 7.2 years, 53.1% males) were enrolled. Imaging and clinical features were analyzed by machine learning to determine predictors of phenoconversion. RESULTS: Machine learning analysis showed that clinical data alone poorly predicted phenoconversion. Presynaptic dopaminergic imaging significantly improved the prediction, especially in combination with clinical data, with 77% sensitivity and 85% specificity in differentiating RBD due to synucleinopathy from non phenoconverted RBD patients, and 85% sensitivity and 86% specificity in discriminating PD-converters from DLB-converters. Quantification of presynaptic dopaminergic imaging showed that an empirical z-score cutoff of -1.0 at the most affected hemisphere putamen characterized RBD due to synucleinopathy patients, while a cutoff of -1.0 at the most affected hemisphere putamen/caudate ratio characterized PD-converters. INTERPRETATION: Clinical data alone poorly predicted phenoconversion in RBD due to synucleinopathy patients. Conversely, presynaptic dopaminergic imaging allows a good prediction of forthcoming phenoconversion diagnosis. This finding may be used in designing future disease-modifying trials. ANN NEUROL 2024;95:1178-1192.
Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging
AbstractA key aim in epidemiological neuroscience is identification of markers to assess brain health and monitor therapeutic interventions. Quantitative susceptibility mapping (QSM) is an emerging magnetic resonance imaging technique that measures tissue magnetic susceptibility and has been shown to detect pathological changes in tissue iron, myelin and calcification. We present an open resource of QSM-based imaging measures of multiple brain structures in 35,273 individuals from the UK Biobank prospective epidemiological study. We identify statistically significant associations of 251 phenotypes with magnetic susceptibility that include body iron, disease, diet and alcohol consumption. Genome-wide associations relate magnetic susceptibility to 76 replicating clusters of genetic variants with biological functions involving iron, calcium, myelin and extracellular matrix. These patterns of associations include relationships that are unique to QSM, in particular being complementary to T2* signal decay time measures. These new imaging phenotypes are being integrated into the core UK Biobank measures provided to researchers worldwide, creating the potential to discover new, non-invasive markers of brain health.
Distinct brain atrophy progression subtypes underlie phenoconversion in isolated REM sleep behaviour disorder.
BACKGROUND: Synucleinopathies include a spectrum of disorders varying in features and severity, including idiopathic/isolated REM sleep behaviour disorder (iRBD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Distinct brain atrophy patterns may already be seen in iRBD; however, how brain atrophy begins and progresses remains unclear. METHODS: A multicentric cohort of 1276 participants (451 polysomnography-confirmed iRBD, 142 PD with probable RBD, 87 DLB, and 596 controls) underwent T1-weighted MRI and longitudinal clinical assessments. Brain atrophy was quantified using vertex-based cortical surface reconstruction and volumetric segmentation. The unsupervised machine learning algorithm, Subtype and Stage Inference (SuStaIn), was used to reconstruct spatiotemporal patterns of brain atrophy progression. FINDINGS: SuStaIn identified two distinct subtypes of brain atrophy progression: 1) a "cortical-first" subtype, with atrophy beginning in the frontal lobes and involving the subcortical structures at later stages; and 2) a "subcortical-first" subtype, with atrophy beginning in the limbic areas and involving cortical structures at later stages. Both cortical- and subcortical-first subtypes were associated with a higher rate of increase in MDS-UPDRS-III scores over time, but cognitive decline was subtype-specific, being associated with advancing stages in patients classified as cortical-first but not subcortical-first. Classified patients were more likely to phenoconvert over time compared to stage 0/non-classified patients. Among the 88 patients with iRBD who phenoconverted during follow-up, those classified within the cortical-first subtype had a significantly increased likelihood of developing DLB compared to PD, unlike those classified within the subcortical-first subtype. INTERPRETATION: There are two distinct atrophy progression subtypes in iRBD, with the cortical-first subtype linked to an increased likelihood of developing DLB, while both subtypes were associated with worsening parkinsonian motor features. This underscores the potential utility of subtype identification and staging for monitoring disease progression and patient selection for trials. FUNDING: This study was supported by grants to S.R. from Alzheimer Society Canada (0000000082) and by Parkinson Canada (PPG-2023-0000000122). The work performed in Montreal was supported by the Canadian Institutes of Health Research (CIHR), the Fonds de recherche du Québec - Santé (FRQS), and the W. Garfield Weston Foundation. The work performed in Oxford was funded by Parkinson's UK (J-2101) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The work performed in Prague was funded by the Czech Health Research Council (grant NU21-04-00535) and by The National Institute for Neurological Research (project number LX22NPO5107), financed by the European Union - Next Generation EU. The work performed in Newcastle was funded by the NIHR Newcastle BRC based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The work performed in Paris was funded by grants from the Programme d'investissements d'avenir (ANR-10-IAIHU-06), the Paris Institute of Neurosciences - IHU (IAIHU-06), the Agence Nationale de la Recherche (ANR-11-INBS-0006), Électricité de France (Fondation d'Entreprise EDF), the EU Joint Programme-Neurodegenerative Disease Research (JPND) for the Control-PD Project (Cognitive Propagation in Prodromal Parkinson's disease), the Fondation Thérèse et René Planiol, the Fonds Saint-Michel; by unrestricted support for research on Parkinson's disease from Energipole (M. Mallart) and the Société Française de Médecine Esthétique (M. Legrand); and by a grant from the Institut de France to Isabelle Arnulf (for the ALICE Study). The work performed in Sydney was supported by a Dementia Team Grant from the National Health and Medical Research Council (#1095127). The work performed in Cologne was funded by the Else Kröner-Fresenius-Stiftung (grant number 2019_EKES.02), the Köln Fortune Program, Faculty of Medicine, University of Cologne, and the "Netzwerke 2021 Program (Ministry of Culture and Science of Northrhine Westphalia State). The work performed in Aarhus was supported by funding from the Lundbeck Foundation, Parkinsonforeningen (The Danish Parkinson Association), and the Jascha Foundation.
Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials.
The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based end point selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA) and related disorders, to compare candidate clinical trial end points. In this multicentre UK study, participants were assessed with serial questionnaires, motor examination, neuropsychiatric and MRI assessments at baseline, 6 and 12 months. Participants were classified by diagnosis at baseline and study end, into Richardson syndrome, PSP-subcortical (PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (PSP-frontal, PSP-speech and language and PSP-CBS subtypes), MSA-parkinsonism, MSA-cerebellar, CBS with and without evidence of Alzheimer's disease pathology and indeterminate syndromes. We calculated annual rate of change, with linear mixed modelling and sample sizes for clinical trials of disease-modifying agents, according to group and assessment type. Two hundred forty-three people were recruited [117 PSP, 68 CBS, 42 MSA and 16 indeterminate; 138 (56.8%) male; age at recruitment 68.7 ± 8.61 years]. One hundred and fifty-nine completed the 6-month assessment (82 PSP, 27 CBS, 40 MSA and 10 indeterminate) and 153 completed the 12-month assessment (80 PSP, 29 CBS, 35 MSA and nine indeterminate). Questionnaire, motor examination, neuropsychiatric and neuroimaging measures declined in all groups, with differences in longitudinal change between groups. Neuroimaging metrics would enable lower sample sizes to achieve equivalent power for clinical trials than cognitive and functional measures, often achieving N < 100 required for 1-year two-arm trials (with 80% power to detect 50% slowing). However, optimal outcome measures were disease-specific. In conclusion, phenotypic variance within PSP, CBS and MSA is a major challenge to clinical trial design. Our findings provide an evidence base for selection of clinical trial end points, from potential functional, cognitive, clinical or neuroimaging measures of disease progression.