[Show abstract][Hide abstract] ABSTRACT: To analyze the texture of T2-weighted magnetic resonance imaging (MRI) of postmortem multiple sclerosis (MS) brain, and to determine whether and how MRI texture correlates with tissue pathology.
Ten brain samples from 3 subjects with MS were examined. Areas of complete, partial, or no loss of Luxol fast blue (myelin) and Bielschowsky (axons) staining were marked on histological images, and matched on corresponding MRI as lesions, diffusely abnormal white matter (DAWM), and normal-appearing white matter (NAWM). The number of CD45(+) cells (inflammation) was also counted. MRI texture was computed using polar Stockwell transform and compared to histology.
Thirty-four lesions, 17 DAWM regions, and 36 NAWM regions were identified. After mixed effects modeling, MRI texture heterogeneity was greater in lesions than in DAWM (p < 0.001) and NAWM (p < 0.001), and was greater in DAWM than in NAWM (p < 0.001); the number of CD45(+) cells was greater in both lesions (p < 0.001) and DAWM (p = 0.005) than in NAWM. In MRI, a gradient of texture heterogeneity was detected in lesions, with gradual tapering toward perilesional NAWM. Moreover, besides univariate correlation with histological markers, texture heterogeneity correlated independently with normalized myelin density (p < 0.01) when random effects were considered. Within sample, MRI texture correlated with myelin and axonal density in 7 of 10 samples (p < 0.01).
Texture analysis performed on routine clinical magnetic resonance images may be a potential measure of tissue integrity. Tissues with more severe myelin and axonal pathology are associated with greater texture heterogeneity. Ann Neurol 2013.
Annals of Neurology 07/2013; 74(1). DOI:10.1002/ana.23867 · 9.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
We investigated the evolution of new multiple sclerosis (MS) lesions over time using frequency shifts of the magnetic resonance (MR) signal.
Twenty patients with relapsing-remitting MS were serially scanned for 6 months at 1-month intervals. Maps of MR frequency shifts were acquired using susceptibility-weighted imaging. New lesions were identified by enhancement with gadolinium (Gd).
Forty new lesions were identified as areas of signal increase on Gd-enhanced scans. Up to 3 months before lesion appearance, the frequency in areas of future Gd enhancement was not detectably different from the frequency in normal-appearing white matter. Rapid increase in MR frequency was observed between 1 month before and 1 month after Gd enhancement. Two months postenhancement and later, the frequency stabilized and remained at a constantly increased level.
These findings suggest that an increase in MR frequency does not simply reflect blood-brain barrier disruption or edema; rather, it reflects a change of tissue architecture as a consequence of new lesion formation. The data demonstrate that the MR frequency of focal MS lesions is increased before the lesions appear on conventional MRI. Unlike many other advanced imaging techniques, the images for frequency mapping can be rapidly acquired at high spatial resolution and standardized on most clinical scanners.
[Show abstract][Hide abstract] ABSTRACT: Objective: We investigated the evolution of new multiple sclerosis (MS) lesions over time using frequency shifts of the magnetic resonance (MR) signal.
Methods: Twenty patients with relapsing-remitting MS were serially scanned for 6
months at one-month intervals. Maps of MR frequency shifts were acquired using sus-
ceptibility weighted imaging. New lesions were identified by enhancement with gadolin-
Results: 40 new lesions were identified as areas of signal increase on Gd-enhanced
scans. Up to three months prior to lesion appearance the frequency in areas of future
Gd-enhancement was not detectably different from the frequency in normal appearing
white matter. Rapid increase in MR frequency was observed between one month before
and one month after Gd-enhancement. Two months post-enhancement and later, the
frequency stabilized and remained at a constantly increased level.
Conclusions: These findings suggest that an increase in MR frequency does not sim-
ply reflect blood brain barrier disruption or edema; rather, it reflects a change of tissue
architecture as a consequence of new lesion formation. The data demonstrate that the
MR frequency of focal MS lesions is increased before the lesions appear on conventional
MRI. Unlike many other advanced imaging techniques, the images for frequency map-
ping can be rapidly acquired at high spatial resolution and standardized on most clinical
[Show abstract][Hide abstract] ABSTRACT: Although multiple sclerosis (MS) lesions have been studied extensively using histology and magnetic resonance imaging (MRI), little is known about diffusely abnormal white matter (DAWM). Diffusely abnormal white matter, regions with reduced mild MRI hyperintensity and ill-defined boundaries, show reduced myelin water fraction, and decreased Luxol fast blue staining of myelin phospholipids, with relative preservation of myelin basic protein and 2',3'-cyclic-nucleotide 3'-phosphohydrolase. Because DAWM may be important in MS disability and progression, further histologic characterization is warranted. The MRI data were collected on 14 formalin-fixed MS brain samples that were then stained for myelin phospholipids, myelin proteins, astrocytes and axons. Diffusely abnormal white matter showed reduced myelin water fraction (-30%, p < 0.05 for 13 samples). Myelin phospholipids showed the most dramatic and consistent histologic reductions in staining optical density (-29% Luxol fast blue and -24% Weil's, p < 0.05 for 13 and 14 samples, respectively) with lesser myelin protein involvement (-11% myelin-associated glycoprotein, -10% myelin basic protein, -8% myelin-oligodendrocyte glycoprotein, -7% proteolipid protein, -5% 2',3'-cyclic-nucleotide 3'-phosphohydrolase, p < 0.05 for 3, 3, 1, 2, and 3 samples, respectively). Axonal involvement was intermediate. Diffusely abnormal white matter lipid and protein reductions occurred independently. These findings suggest a primary lipid abnormality in DAWM that exceeds protein loss and is accompanied by axonal degeneration. These phenomena may be important in MS pathogenesis and disease progression, which is prominent in individuals with DAWM.
[Show abstract][Hide abstract] ABSTRACT: We wished to demonstrate the feasibility of performing diagnostic mitochondrial DNA (mtDNA) analysis on biopsies of the orbicularis oculi muscle in patients with a chronic progressive external ophthalmoplegia (CPEO) phenotype and suspicion of an underlying mitochondrial disorder.
Case series of three patients who underwent ptosis surgery and had simultaneous biopsy of the orbicularis oculi muscle because of a suspicion of a mitochondrial disorder. Orbicularis muscle samples were divided into two pieces at the time of biopsy. The first was snap-frozen in liquid nitrogen, DNA was extracted and mtDNA deletion analysis was performed by two complementary methods (long PCR and Southern blot analysis). The second piece of muscle was assessed using routine histopathology, electron microscopy and immuno-histochemical analysis.
Three patients with clinical features of CPEO, without any positive family history, underwent orbicularis muscle biopsies at time of eyelid ptosis surgery. All biopsies were adequate to conduct histopathological and immuno-histochemical analysis, which showed evidence of abnormal muscle structure and function. mtDNA was successfully extracted from all biopsies, and long PCR and Southern blot analysis confirmed diagnostic large single mtDNA deletions in all three cases.
Orbicularis oculi muscle biopsies are useful in patients with CPEO to perform mtDNA analysis, thus avoiding a separate biopsy of skeletal muscle elsewhere.
The British journal of ophthalmology 08/2012; 96(10):1296-9. DOI:10.1136/bjophthalmol-2012-301853 · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The advent of magnetic resonance imaging (MRI) has revolutionized concepts of the pathogenesis of multiple sclerosis (MS). Magnetic resonance imaging provides the ability to delineate the evolution of the disease process over time; captured static snapshots can then be used in pathologic correlations studies. Certain patterns in the 2- or 3-dimensional MRI sphere correlate very well with similar patterns of histopathology. A multimodality approach that makes use of numerous MRI techniques can lead to significant insights into the nature of the changes in the CNS. MRI-pathology correlation studies in MS are being performed using newer MRI techniques as they become available. Such correlations and basic histopathologic studies have shown abnormalities in MS far beyond the well-documented changes in the plaque and have brought into question the dogma that MS is an initially inflammatory nondegenerative disease. This review briefly outlines technical considerations in MRI-pathology correlative studies and describes the past and current status of our ability to correlate focal and diffuse changes on the MRI with neuropathologic findings in MS patients.
Journal of Neuropathology and Experimental Neurology 08/2012; 71(9):762-78. DOI:10.1097/NEN.0b013e3182676388 · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The histopathology of multiple sclerosis (MS), the most common demyelinating disorder, is the main focus of this review. MS is characterized by inflammatory demyelination, accompanied by gliosis. The MS plaque can show ongoing active demyelination, which can be accompanied by varying degrees of remyelination, or be quiescent. The current concept that MS is an autoimmune disease of myelin has been challenged by recent studies, and it is becoming increasingly clear that neurodegeneration is a significant component of the disease and may largely account for its progressive disability. Other disorders related to MS that are briefly discussed here are acute disseminated encephalomyelitis, acute haemorrhagic leucoencephalitis, neuromyelitis optica and progressive multifocal leucoencephalopathy.
[Show abstract][Hide abstract] ABSTRACT: The pathological basis of diffusely abnormal white matter (DAWM) in multiple sclerosis (MS) has not been elucidated in detail, but may be an important element in disability and clinical progression.
Fifty-three subjects with MS were examined with T₁, multi-echo T₂ and magnetization transfer (MT). Twenty-three samples of formalin-fixed MS brain tissue were examined with multi-echo T₂ and subsequently stained for myelin phospholipids using luxol fast blue, for axons using Bielschowsky, immunohistochemically for the myelin proteins myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3' phosphohydrolase (CNP) and for astrocytes using glial fibrillary acidic protein (GFAP). Regions of interest in DAWM were compared with normal appearing white matter.
Fourteen of 53 subjects with MS in the in vivo study showed the presence of DAWM. Subjects with DAWM were found to have a significantly lower Expanded Disability Status Scale (EDSS) and shorter disease duration (DD) when compared with subjects without DAWM (EDSS: 1.5 versus 3.0, p = 0.031; DD: 5.4 versus 10.3 years, p = 0.045). DAWM in vivo had reduced myelin water and MT ratio, and increased T₂ and water content. Histological analysis suggests DAWM, which shows a reduction of the myelin water fraction, is characterized by selective reduction of myelin phospholipids, but with a relative preservation of myelin proteins and axons.
These findings suggest that the primary abnormality in DAWM is a reduction or perturbation of myelin phospholipids that correlates with a reduction of the myelin water fraction.
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis (MS) has been classically regarded as an inflammatory demyelinating disease of the central nervous system. In recent years, the classification and pathogenesis of the disease have become controversial, particularly with respect to whether an individual patient demonstrates a single or multiple pathogenetic mechanisms in the establishment of the focal plaque of MS. It is also becoming increasingly apparent that there is a significant neurodegenerative component in the disease, involving not only plaques but the non-plaque parenchyma as well. Magnetic resonance imaging, together with histopathologic studies, will continue to shed light on the pathogenesis of these focal and diffuse abnormalities in MS.
The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 09/2010; 37 Suppl 2(S2):S5-15. DOI:10.1017/S0317167100022381 · 1.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mechanism of action of deep brain stimulation (DBS) in the alleviation of tremor in multiple sclerosis (MS) and other neurological disorders is unknown. Moreover, whether the trauma accompanying this surgery is responsible for the induction of new MS plaques is controversial. Here we report the first description of the post-mortem imaging and pathologic findings in the brain of a MS patient who underwent thalamic DBS for the treatment of MS-induced tremor. MR imaging of formalin-fixed brain slices was carried out at 1.5, 3 and 7 Tesla and correlated with the histopathology. There were numerous demyelinative plaques in the white mater, cortex and deep gray matter. There were no plaques along the DBS tract within the sections that sampled the deep hemispheric white matter. However, deep within the thalamus focal demyelination approximated the tract, particularly in the region corresponding to the electrical field. The findings in this single case raise the possibility that focal demyelination may be induced by the electrical field and this may be responsible for long-lasting alleviation of tremor in the absence of continued electrostimulation.
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis (MS) has neurodegenerative features including neuronal and axonal loss and widespread atrophy of the brain and spinal cord. The cause of this neurodegeneration has been largely attributed to inflammation, but other mechanisms, including those associated with classic neurodegenerative diseases such as the alpha-synucleinopathies, might also be involved in MS pathogenesis. In this study, 96 brain lesions containing varying degrees of inflammatory activity from 12 autopsied MS cases were compared with corresponding regions from 6 neuropathologically normal controls; 2 cerebral biopsy lesions from an MS patient were also studied. We found alpha-synuclein immunoreactivity in the cytoplasm of cells in MS lesions with inflammatory activity but not in control samples. alpha-Synuclein-immunoreactive cells were identified in active (15/15 lesions in the brainstem, 9/13 in cerebral hemispheres) and chronic active (14/15 in the brainstem, 12/22 in cerebral hemispheres) lesions but were absent in chronic inactive lesions (0/31); the greater immunoreactivity in brainstem compared with cerebral hemisphere lesions was significant (p < 0.05). Double-immunofluorescence staining revealed localization of alpha-synuclein immunoreactivity mostly in neurons, microglia/macrophages, and oligodendrocytes, and only rarely in astrocytes. The results suggest that alpha-synuclein expression regulated by inflammatory signals may contribute to neurodegenerative processes in MS lesions.
Journal of Neuropathology and Experimental Neurology 02/2009; 68(2):179-89. DOI:10.1097/NEN.0b013e318196e905 · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myelin water imaging (MWI) promises to be invaluable in understanding neurological diseases like MS. However, a limitation of MWI is signal to noise ratio. Recently, a number of investigators have performed MWI at field strengths higher than 1.5 T. Our goal was to determine if myelin water imaging at increased SNR, arising from the use of a small bore 7 T MR system with optimized coil geometry, enables the production of superior myelin water maps with increased spatial detail and enables better correlations with histology. Ten formalin-fixed MS brain samples underwent a 32-echo T(2) relaxation experiment which measured myelin water fraction (MWF) on a 7-T animal MRI scanner. MWF correlated strongly qualitatively and quantitatively with luxol fast blue staining for myelin [mean (range): R(2)=0.78 (0.56-0.95), p<0.0001]. The quality and detail of 7 T myelin water maps were far superior to that previously seen at 1.5 T, allowing for visualization of fine structures such as the normal prominent myelination of the deeper cortical layers, the alveus of the hippocampus and rings of preserved myelin in a concentric Balo's lesion. 7 T imaging will allow detailed assessment of myelin pathology to a degree not possible with lower field strengths.
[Show abstract][Hide abstract] ABSTRACT: Lipoatrophy and localized panniculitis have been described as rare complications of daily subcutaneous glatiramer acetate injections for the treatment of relapsing-remitting multiple sclerosis (MS). We describe the biopsies from two MS patients in a single neurologist's practice who developed clinical lesions of lipoatrophy at the sites of subcutaneous glatiramer acetate injections. These biopsies showed a lobular panniculitis with lipoatrophy that more closely resembled lupus panniculitis than previous reports of localized panniculitis at glatiramer acetate injection sites. In one case, the area of clinical lipoatrophy continued to enlarge for 6 months after stopping glatiramer acetate therapy, before stabilizing at its current size for the last 8 months. Injection site reactions to glatiramer acetate should be considered in the differential diagnosis of biopsies that show a lupus panniculitis-like appearance. Our observations indicate that glatiramer acetate induced panniculitis is common and may continue to progress after therapy has stopped. In this single neurologist's practice, 64% of the patients receiving daily glatiramer acetate injections had clinical evidence of lipoatrophy or panniculitis. Of 100 consecutive patients receiving therapy for MS between February and November 2006, 14 patients were on glatiramer acetate, 9 of whom had clinical lipoatrophy.
[Show abstract][Hide abstract] ABSTRACT: While conventional magnetic resonance imaging (MRI) has long been used to study multiple sclerosis (MS), more sensitive and specific approaches to studying both MS lesions and normal appearing white matter (NAWM) are needed to gain a better understanding of the pathogenesis of the disease. Two MRI techniques thought to offer insight regarding myelin and axonal integrity are T(2) relaxation and diffusion tensor imaging (DTI). In this study, metrics obtained from T(2) relaxation (specifically myelin water content (MWC) and long-T(2) fraction) and DTI experiments (in particular the fractional anisotropy, mean diffusivity , parallel diffusivity lambda(||), and perpendicular diffusivity lambda(perpendicular)) were compared for 19 MS patients within both lesion and contralateral NAWM with the goal of better understanding how each of the measures are affected by pathology. In particular, it was successfully determined that the detection of a long-T(2) signal within an MS lesion is indicative of a different underlying pathology than is present in lesions without long-T(2) signal. All of the diffusion metrics were significantly different in lesions with a long-T(2) signal than in those without. While no significant correlations were found between MWC and , lambda(||) or lambda(perpendicular) in NAWM (R(2)=0.02-0.04, p>0.07), and only weak correlations were found in lesions without long-T(2) signal (R(2)=0.05-0.14, p<0.04), strong correlations were observed in lesions exhibiting long-T(2) signal (R(2)=0.54-0.61, p<0.0001).
[Show abstract][Hide abstract] ABSTRACT: Multi-echo T(2) measurements are invaluable in studying brain pathology in multiple sclerosis (MS). In addition to information about myelin water and total water content, the T(2) distribution has the potential to detect additional water reservoirs arising from other sources such as inflammation or edema. The purpose of this study was to better define the T(2) distribution in MS lesions and normal appearing white matter (NAWM) with particular emphasis on the characterisation of longer T(2) components. Magnetisation transfer (MT), T(1) and 48-echo T(2) relaxation data were acquired in 20 MS subjects and regions of interest were drawn in lesions and NAWM. Twenty-seven out of 107 lesions exhibited signal with a markedly prolonged T(2) (200-800 ms). Lesions with a Long-T(2) signal also exhibited a longer geometric mean T(2) (GMT(2)), increased water content (WC), higher T(1), reduced magnetisation transfer ratio (MTR) and decreased myelin water fraction (MWF) than lesions without a Long-T(2) signal. Those subjects with Long-T(2) lesions had a significantly longer disease duration than subjects without this lesion subtype. A strong correlation was observed between T(1) and Long-T(2) fraction, while a slightly weaker relationship was found for GMT(2), MTR and MWF with Long-T(2) fraction. A potential source of the Long-T(2) signal is an increase in extracellular water. This study supports the usefulness of increasing the data acquisition window of the multi-echo T(2) relaxation sequence to better characterise the T(2) decay in MS.
Journal of Neurology 12/2007; 254(11):1579-87. DOI:10.1007/s00415-007-0595-7 · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To describe what, if any, specific long T(2)-related abnormalities occur in the white matter of subjects with either phenylketonuria (PKU) or multiple sclerosis (MS).
The 48-echo T(2) relaxation data (maximum TE = 1.12 sec) were acquired from 15 PKU subjects, 20 MS subjects, and 15 healthy volunteers. Regions of interest were drawn in diffuse white matter hyperintensities (DiffWM), lesions, normal-appearing white matter (NAWM), and normal white matter. Long T(2) maps (200 msec < T(2) < 800 msec) were created for each subject.
A new water reservoir with a markedly prolonged T(2) peak was identified in DiffWM and NAWM in 12 out of 15 subjects with PKU and a long T(2) signal was also seen in 23/97 lesions in 50% of subjects with MS. Additionally, a long T(2) component was observed in the corticospinal tracts of 10 healthy volunteers. The characteristics of the long T(2) signal were unique for each subject group. Potential sources of this signal include vacuolation and increases in extracellular water.
This study supports the usefulness of increasing the data acquisition window of the multiecho T(2) relaxation sequence to better characterize the T(2) decay from pathological brain.
Journal of Magnetic Resonance Imaging 10/2007; 26(4):1117-21. DOI:10.1002/jmri.21132 · 3.21 Impact Factor