Milena Stosic

Smoking is associated with increased lesion volumes and brain atrophy in multiple sclerosis

Background: Cigarette smoking has been linked to higher susceptibility and increased risk of progressive multiple sclerosis (MS). The effects of smoking on MRI characteristics of patients with MS have not been evaluated. Objectives: To compare the MRI characteristics in cigarette smoker and nonsmoker patients with MS. Methods: We studied 368 consecutive patients with MS (age 44.0 ±SD 10.2 years, disease duration 12.1 ± 9.1 years) comprising 240 never-smokers and 128 (34.8%) ever-smokers (currently active and former smokers). The average number of packs per day smoked (±SD) was 0.95 ± 0.65, and the mean duration of smoking was 18.0 ± 9.5 years. All patients obtained full clinical and quantitative MRI evaluation. MRI measures included T1, T2, and gadolinium contrast-enhancing (CE) lesion volumes (LVs) and measures of central, global, and tissue-specific brain atrophy. The associations between smoking status and MRI measurements were assessed in regression analysis. Results: Smoking was associated with increased Expanded Disability Status Scale (EDSS) scores (p = 0.004). The median EDSS scores (interquartile range) in the ever-smoker group and the active-smoker group were both 3.0 (2.0), compared with 2.5 (2.5) in never-smokers. There were adverse associations between smoking and the lesion measures including increased number of CE lesions (p < 0.001), T2 LV (p = 0.009), and T1 LV (p = 0.003). Smoking was associated with decreased brain parenchymal fraction (p = 0.047) and with increases in the lateral ventricle volume (p = 0.001) and third ventricle width (p = 0.023). Conclusions: Smoking is associated with increased blood–brain barrier disruption, higher lesion volumes, and greater atrophy in multiple sclerosis.

The place of conventional MRI and newly emerging MRI techniques in monitoring different aspects of treatment outcome

Magnetic resonance imaging (MRI) is the most important paraclinical measure for assessing and monitoring the pathologic changes implicated in the onset and progression of multiple sclerosis (MS). Conventional MRI sequences, such as T1-weighted gadolinium (Gd) enhanced and spin-echo T2-weighted imaging, only provide an incomplete picture of the degree of inflammation and underlying neurodegenerative changes in this disease. Two- and three-dimensional fluid-attenuated inversion recovery and double inversion recovery sequences allow better identification of cortical, periventricular and infratentorial lesions. Ultra-high field strength MRI has the potential to detect subpial cortical and deep gray matter lesions. Unenhanced T1-weighted imaging can reveal hypointense black holes, a measure of chronic neurodegeneration. Magnetization transfer imaging (MTI) is increasingly used to characterize the evolution of MS lesions and normal-appearing brain tissue. Evidence suggests that the dynamics of magnetization transfer changes correlate with the extent of demyelination and remyelination. Magnetic resonance spectroscopy, which provides details on tissue biochemistry, metabolism, and function, also has the capacity to reveal neuroprotective mechanisms. By measuring the motion of water, diffusion imaging can provide information about the orientation, size, and geometry of tissue damage in white and gray matter. These advanced non-conventional MRI techniques relate better to clinical impairment, disease progression, accumulation of disability, and have the potential to detect neuroprotective effects of treatment. Although detecting the status of neuronal integrity using MRI techniques continues to improve, a “gold standard” model remains to be established.

Gender-related differences in MS: a study of conventional and nonconventional MRI measures

Background Studies showed gender-associated differences in multiple sclerosis (MS) disease evolution and in the evolution of conventional magnetic resonance imaging (MRI) findings. Objective The aim of this study was to investigate gender differences according to a number of conventional and nonconventional MRI measures in patients with MS. Methods We examined 763 consecutive patients with MS [499 (19.2% men) relapsing-remitting (RR), 230 (24.8% men) secondary-progressive, and 34 (44.1% men) primary-progressive], 32 (21.9% men) patients with clinically isolated syndrome (CIS), and 101 (30.7% men) normal controls (NC). Patients were assessed using conventional and nonconventional MRI measures. Gender-related MRI differences were investigated using general linear model analysis, corrected for MS disease type. Results In the total MS group, male patients showed lower normalized peripheral gray matter (GM) (P < 0.001) and normalized GM (P = 0.011) volumes than female patients. Female patients presented lower normalized white matter (WM) volumes (P = 0.011). These gender effects were not observed in NC. Male patients also showed more advanced central atrophy (P = 0.022). In RRMS male patients, there was also a higher lateral ventricle volume (P = 0.001). The GM-WM normalized ratio was lower for male patients with MS compared with male NC (0.97 vs. 1.09, P < 0.001) but not in patients with CIS compared with NC. Conclusions There were no significant gender-related differences regarding nonconventional MRI measures. GM and central atrophy are more advanced in male patients, whereas WM atrophy is more advanced in female patients. These gender-related MRI differences may be explained by the effect of sex hormones on brain damage and repair mechanisms.

Neuromyelitis optica immunoglobulins as a marker of disease activity and response to therapy in patients with neuromyelitis optica

Objective To determine whether neuromyelitis optica (NMO) immunoglobulin (IgG) antibody status in NMO/Devic’s disease patients followed prospectively is persistent or can change relative to the clinical status and/or response to therapy. Design A cross-sectional group of patients with NMO, relapsing extensive longitudinal transverse myelitis (RLETM) or optico-spinal multiple sclerosis (OSMS) were evaluated for the presence of NMO IgG antibodies. Repeated evaluation was made in all NMO/RLETM patients and in a subgroup of OSMS patients. Setting Baird Multiple Sclerosis Center, Buffalo, New York, an academic multiple sclerosis center. Results Out of a consecutive cohort of 38 patients evaluated for the presence of NMO IgG, 12 had NMO and 26 had OSMS. Five of the 12 NMO/RLETM patients were NMO IgG positive at the time of their initial evaluation. Four of these patients were repeatedly tested for NMO IgG: two of these became negative and two remained positive. One patient who was initially negative became positive during an acute event and again became negative during the stable disease phase following treatment. A positive test result was associated with active disease, whereas a negative NMO IgG result was consistently found in stable, long-term treated patients. None of the OSMS patients were positive for NMO IgG even during acute attacks. Conclusions NMO IgG antibodies are associated with active NMO/RLETM. A well-controlled stable disease usually under effective immunosuppressive therapy can transform the NMO IgG to a negative status. Repeated NMO IgG testing should be considered as a useful biological marker for monitoring NMO/RLETM disease and or response to therapy.

Signal abnormalities on 1.5 and 3 Tesla brain MRI in multiple sclerosis patients and healthy controls. A morphological and spatial quantitative comparison study

Previous studies in patients with multiple sclerosis (MS) revealed increased lesion count and volume on 3 T compared to 1.5 T. Morphological and spatial lesion characteristics between 1.5 T and 3 T have not been examined. The aim of this study was to investigate the effect of changing from a 1.5 T to a 3 T MRI scanner on the number, volume and spatial distribution of signal abnormalities (SA) on brain MRI in a sample of MS patients and normal controls (NC), using pair- and voxel-wise comparison procedures. Forty-one (41) MS patients (32 relapsing-remitting and 9 secondary-progressive) and 38 NC were examined on both 1.5 T and 3 T within one week in random order. T2-weighted hyperintensities (T2H) and T1-weighted hypointensities (T1H) were outlined semiautomatically by two operators in a blinded fashion on 1.5 T and 3 T images. Spatial lesion distribution was assessed using T2 and T1 voxel-wise SA probability maps (SAPM). Pair-wise analysis examined the proportion of SA not simultaneously outlined on 1.5 T and 3 T. A posteriori unblinded analysis was conducted to examine the non-overlapping identifications of SA between the 1.5 T and 3 T. For pair-wise T2- and T1-analyses, a higher number and individual volume of SA were detected on 3 T compared to 1.5 T (p<0.0001) in both MS and NC. Logistic regression analysis showed that the likelihood of missing SA on 1.5 T was significantly higher for smaller SA in both MS and NC groups. SA probability map (SAPM) analysis revealed significantly more regionally distinct spatial SA differences on 3 T compared to 1.5 T in both groups (p<0.05); these were most pronounced in the occipital, periventricular and cortical regions for T2H. This study provides important information regarding morphological and spatial differences between data acquired using 1.5 T and 3 T protocols at the two scanner field strengths.

Use of perfusion- and diffusion-weighted imaging in differential diagnosis of acute and chronic ischemic stroke and multiple sclerosis

Abstract Objective: To investigate differences in lesions and surrounding normal appearing white matter (NAWM) by perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) in patients with acute and chronic ischemic stroke and multiple sclerosis (MS). Methods: Study subjects included 45 MS patients, 22 patients with acute ischemic stroke and 20 patients with chronic ischemic stroke. All subjects underwent T2-weighted imaging (WI), flair attenuated inversion recovery (FLAIR), DWI and dynamic contrast enhanced PWI. Apparent diffusion coefficient (ADC) and mean transit time (MTT) maps were generated and values were calculated in the acute and chronic ischemic and demyelinating lesions, and in NAWM for distances of 5, 10 and 15 mm. Fifty-three acute ischemic and 33 acute demyelinating lesions, and 775 chronic ischemic and 998 chronic demyelinating lesions, were examined. Univariate, multivariate and data mining analyses were used to examine the feasibility of a prediction model between different lesion types. Correctly and incorrectly classified lesions, true positive (TP), false positive (FP) and precision rates were calculated. Results: Patients with acute ischemic lesions presented more prolonged mean MTT values in lesions (p=0.002) and surrounding NAWM for distances of 5, 10 and 15 mm (all p<0.0001) than those with acute demyelinating lesions. In multinomial logistic regression analysis, 65 of 86 acute lesions were correctly classified (75.6%). The TP rates were 81.1% for acute ischemic lesions and 66.7% for acute demyelinating lesions. The FP rates were 33.3% for acute ischemic and 18.9% for acute demyelinating lesions. The precision was 79.6% for classification of acute ischemic lesions and 68.8% for prediction of acute demyelinating lesions. The logistic model tree decision algorithm revealed that prolonged MTT of surrounding NAWM for a distance of 15 mm (≥7459.2 ms) was the best classifier of acute ischemic versus acute demyelinating lesions. Patients with chronic ischemic lesions presented higher mean ADC (p<0.0001) and prolonged MTT (p=0.013) in lesions, and in surrounding NAWM for distances of 5, 10 and 15 mm (all p<0.0001), compared to the patients with chronic demyelinating lesions. Data mining analyses did not show reliable predictability for correctly discerning between chronic ischemic and chronic demyelinating lesions. The precision was 56.7% for classification of chronic ischemic and 58.9% for prediction of chronic demyelinating lesions. Discussion: We found prolonged MTT values in lesions and surrounding NAWM of patients with acute and chronic ischemic stroke when compared to MS patients. The use of PWI is a promising tool for differential diagnosis between acute ischemic and acute demyelinating lesions. The results of this study contribute to a better understanding of the extent of hemodynamic abnormalities in lesions and surrounding NAWM in patients with MS.

The rs2030324 SNP of brain-derived neurotrophic factor (BDNF) is associated with visual cognitive processing in multiple sclerosis.

PURPOSE To investigate the associations between the rs2030324 SNP of brain-derived neurotrophic factor (BDNF) and neuropsychological (NP) test measures in multiple sclerosis (MS) patients. BACKGROUND BDNF regulates the survival of neuronal and non-neuronal cells and plays a critical role in neurochemical processes underlying learning and memory. METHODS A total of 209 MS patients (161 females; 48 males) underwent brain MRI and genotyping for BDNF rs2030324. The NP testing (n=108) assessed processing speed, working memory, new learning and executive control. The MRI measurements included T1 and T2 lesion volume, whole brain, white and gray matter volumes, magnetization transfer imaging and regional subcortical brain volumes. RESULTS The T/T rs2030324 genotype group performed poorly on the Brief Visuospatial Memory Test-Revised (p=0.031) and the Symbol Digit Modalities Test (p=0.045) compared to the C/C genotype group. Because these NP tests both involve visual processing, the relationship with the volume of the thalamus was assessed. The BDNF rs2030324 genotype was associated with the volume of the left thalamus (p=0.036). There were no significant associations with whole brain lesional and atrophy MRI measures. CONCLUSIONS The C allele of BDNF rs2030324 is associated with protection against visual cognitive processing deficits via mechanisms that appear associated with the volume of the thalamus.

MRI characteristics of patients with antiphospholipid syndrome and multiple sclerosis

MRI findings of primary anti-phospholipid antibody syndrome (PAPLS) are difficult to distinguish from those of multiple sclerosis (MS). Only a few previous studies have compared conventional and non-conventional MRI findings in MS and PAPLS patients. In addition, MRI differences between anti-phospholipid antibody (APLA) positive (+) and APLA negative (−) MS patients have not been reported. Therefore, the aim of this study was to investigate the differences in MRI measures among patients with PAPLS, MS and normal control (NC) subjects. We also explored non-conventional MRI measures in APLA+ and APLA− MS patients. Forty-nine (49) consecutive MS patients among whom 39 had relapsing-remitting (RR) and 10 secondary-progressive (SP) disease course, 30 patients with PAPLS and 49 NC were enrolled. Twenty-eight (28) MS patients were APLA+. MRI measures of T1- and T2-lesion volumes (LV) and brain atrophy, including fractions of whole brain (BPF), gray matter (GMF) and white matter (WMF), were evaluated. The magnetization transfer ratio (MTR) of T2- and T1-LVs and different normal-appearing brain tissue (NABT) compartments as well as diffusion-weighted imaging of whole brain mean parenchyma diffusivity (MPD) were obtained. MS patients differed significantly from NC in all MRI measures. PAPLS patients differed from NC in their T2-LV, in MTR measures and in MPD. When MS patients were compared to PAPLS patients, they showed significantly higher T2- and T1-LVs and T2-LV MTR, lower BPF and GMF and higher MPD. APLA+ RR and SPMS (all APLA+) patients showed significantly higher T2-LV, lower GMF, lower normal-appearing gray matter MTR and higher MPD when compared to APLA− patients. The results indicate that brain abnormalities can be detected in PAPLS patients with non-conventional MRI. MRI reveals more profound injury in patients with MS versus PAPLS. APLA mediates heterogeneous cerebral pathology that remains to be further investigated.

Glatiramer acetate recovers microscopic tissue damage in patients with multiple sclerosis. A case-control diffusion imaging study.

Traditional magnetic resonance imaging (MRI) techniques have contributed to the management of multiple sclerosis (MS) but are limited in their ability to detect neuronal damage. Advanced MRI metrics provide assessment of microscopic neuronal changes; however, few studies have examined the effects of MS therapies on these measures. This prospective, open-label, observational study evaluated the effect of subcutaneous glatiramer acetate (GA) 20mg/day on the 1- and 2-year changes in diffusion-weighted imaging (DWI) measures in patients with relapsing-remitting (RR) MS and in age- and sex-matched healthy controls (HC). Inclusion criteria were age 18-65, RR disease course, expanded disability status scale (EDSS) score ≤5.5 and disease duration<20 years. MS patients and HC underwent 1.5T MRI scans and clinical examinations at baseline and at 1- and 2-year follow-up. Nineteen RRMS patients and 16 HC completed the 1-year follow-up and 16 MS patients and 13 HC the 2-year follow-up of the study. In MS patients, treatment with GA promoted recovery of DWI mean parenchymal diffusivity (MPD) at year 1 (-7.1%, p=0.007) and at year 2 (-10.1%, p=0.028). The recovery of DWI MPD was significantly higher in MS patients compared to HC at year 1 (p=0.01) and year 2 (p<0.001). GA promoted recovery of DWI entropy at 2 years (-1.2%, p=0.018). No significant DWI MPD and entropy changes were observed in HC over the follow-up. No significant deterioration in magnetization transfer ratio occurred over the follow-up in MS patients and HC. Patients on GA and HC did not develop significant global or regional atrophy over 2 years. GA significantly improved microscopic tissue damage in the brain, as measured by DWI over the 1- and 2-year follow-up.

Role of Imaging Techniques in Discerning Neurobehavioral Changes in Ischemic, Neurodegenerative and Demyelinating Disorders

Magnetic resonance imaging (MRI) is the most important paraclinical measure for assessing and monitoring the pathologic changes implicated in the onset and progression of demyelinating and ischemic disorders. Conventional MRI sequences, such as T2-weighted imaging are unable to provide full details about the degree of inflammation and underlying neu- rodegenerative changes. Newer non-conventional MRI techniques have the potential to detect clinical impairment, disease progression, accumulation of disability, and the neuroprotective effects of treatment. The measurement of brain atrophy seems to be of growing clinical relevance as a biomarker of the disease process. Atrophy should now be included as a secondary end- point in trials of therapies aimed at limiting disease progression. Magnetization transfer imaging is increasingly used to characterize the evolution of lesions and normal-appearing brain tissue. Magnetic resonance spec-troscopy, which provides details on tissue biochemistry, metabolism, and function, also has the capacity to reveal neurodegeneration and neuroprotective mechanisms. By measuring the motion of water, diffusion imaging can provide information about the orientation, size, and geometry of tissue damage in white and gray matter. Functional MRI and other nuclear functional techniques may help clarify the brains plasticity- and receptor-dependent compensatory mechanisms in patients with a variety of neurologic disorders. New techniques that might bring new information to the field include studies of microglial activation and studies using multiple single photon emission computed tomography (SPECT) and positron emission tomography (PET) tracers. All these techniques are useful in establishing diagnosis, monitoring disease activity, measuring therapeutic effect and explaining the development of disability in the short-and long-term. The role of these techniques in discerning neurobehavioral and neuropsychiatric symptoms in neurodegenerative (emphasizing Parkinsons Disease and Dementia with Lewy Bodies), ischemic and demyelinating disorders will be discussed.