Fen Bao

Axonal metabolic recovery and potential neuroprotective effect of glatiramer acetate in relapsing-remitting multiple sclerosis

Glatiramer acetate (GA) is a disease-modifying therapy for relapsing-remitting multiple sclerosis (RRMS) with several putative mechanisms of action. Currently, there is paucity ofin vivo human data linking the well-established peripheral immunologic effects of therapy with GA to its potential effects inside the central nervous system (CNS). Brain proton magnetic resonance spectroscopy (MRS) allows in vivo examination of axonal integrity by quantifying the resonance intensity of the neuronal marker N-acetylaspartate (NAA). In a pilot study to investigate the effect of GA on axonal injury, we performed combined brain magnetic resonance imaging (MRI) and MRS studies in 18 treatment naïve RRMS patients initiating therapy with GA at baseline and annually for two years on therapy. A small group of four treatment naïve RRMS patients, electing to remain untreated, served as controls. NAA/Cr was measured in a large central brain volume of interest (VOI) as well as the normal appearing white matter (NAWM) within the VOI. After two years, NAA/Cr in the GA-treated group increased significantly by 10.7% in the VOI (2.179±0.26 versus 1.969±0.24, P=0.03) and by 7.1% in the NAWM (2.239±0.26 versus 2.089±0.31, P=0.04). In the untreated group, NAA/Cr decreased by 8.9% at two years in the VOI (2.019±0.16 versus 1.839±0.21, P=0.03) and 8.2% in the NAWM (2.079±0.24 versus 1.909±0.29, P=0.03). Our data shows that treatment with GA leads to axonal metabolic recovery and protection from sub-lethal axonal injury. These results support an in situ effect of GA therapy inside the CNS and suggest potential neuroprotective effects of GA.

Progressive Multifocal Leukoencephalopathy and Relapsing-Remitting Multiple Sclerosis: A Comparative Study

OBJECTIVE To identify clinical and magnetic resonance imaging (MRI) features that distinguish progressive multifocal leukoencephalopathy (PML) from relapsing-remitting multiple sclerosis (RRMS). DESIGN Retrospective medical record review. SETTING Two urban teaching hospitals in Detroit, Michigan. Patients Forty-five confirmed PML cases and 100 patients with RRMS. MAIN OUTCOME MEASURES Clinical and MRI features distinguishing PML from RRMS. RESULTS Overall, monosymptomatic presentations were more common in multiple sclerosis (MS) than PML (85% vs 47%; P < .01). However, patients with PML presented more often with hemiparesis (24% vs 5%; P = .001) and altered mentation (19% vs 0%; P < .0001), whereas brainstem (2% vs 18%; P = .007) presentations were more common in patients with RRMS. Spinal cord and optic neuritis presentations were seen in 18% and 33% of patients with RRMS, respectively, but not in patients with PML (m < .0001). Brain MRI scans, available in 35 (78%) PML cases, revealed 7 lesion types. Large, confluent T2-weighted lesions (74% vs 2%; P < .0001) and deep gray matter lesions (31% vs 7%; P < .001) were more frequent in patients with PML than patients with RRMS. Crescentic cerebellar lesions (23% vs 0%; P < .001) were seen only in patients with PML. Gadolinium-enhancing (23%), transcallosal (9%), and periventricular (9%) lesions were noted in patients with PML. Brain magnetization transfer ratio (MTR) was low in both PML and MS lesions. However, normal-appearing brain tissue MTR in PML was higher than normal-appearing brain tissue MTR in RRMS (44.15% vs 41.04%; P = .002), suggesting that PML may be relatively more focal than MS. CONCLUSIONS There appear to be differences between the clinical and MRI characteristics of PML and RRMS, which may help distinguish new MS activity from PML. Magnetization transfer ratio studies may provide additional clues in improving early detection of PML in patients with preexisting MS and warrant further investigation.

Long-term study of brain 1H-MRS study in multiple sclerosis: Effect of glatiramer acetate therapy on axonal metabolic function and feasibility of long-term 1H-MRS monitoring in multiple sclerosis

Glatiramer acetate (GA) has several putative mechanisms of action with the potential of limiting sublethal axonal injury in the central nervous system (CNS). Brain proton magnetic resonance spectroscopy (1H‐MRS) allows in vivo examination of axonal integrity by quantifying the neuronal marker N‐acetylaspartate (NAA), often expressed as a ratio to creatine (Cr). We showed that treatment with GA led to improvement in NAA/Cr over a 2‐year period. We now report the results of this ongoing study after 4 years of annual brain 1H‐MRS examinations. Compared to baseline, at year 4, patients receiving continuous GA therapy showed a 12.7% increase in NAA/Cr and (P= .03) in the multivoxel brain volume of interest (VOI) studied and by 9.6% (P= .04) in the normal‐appearing white matter within the VOI. Three patients in the control group who began therapy with GA during the course of the study showed similar increases in NAA/Cr after the first year of therapy. These data support the long‐term effect of GA on maintaining axonal metabolic function and protection from sublethal injury as well as the feasibility of employing brain 1H‐MRS in long‐term investigative studies in MS.

Acute transverse myelitis with normal brain MRI Long-term risk of MS

ObjectiveTo investigate the long-term risk of developing MS in patients presenting with acute transverse myelitis (ATM) and normal brain MRI scans at onset.MethodsWe studied 58 ATM patients with normal brain MRI at presentation for up to 5 years with serial neurologic and imaging studies. All patients underwent CSF analysis at onset which was defined positive if two or more IgG oligoclonal bands and/or elevated IgG index were present. Brain and spinal cord MRI scans were obtained every 6 months for the first 2 years, and annually thereafter unless the patient experienced a second neurologic attack different from the initial episode to confirm CDMS or there was demonstration of MRI lesions confirming dissemination in time and space to fulfill McDonald imaging criteria to diagnose MS.ResultsSeventeen of 58 (29%) patients developed MS of which 7 (41%) patients developed CDMS and 10 (59%) developed MS using McDonald Imaging Criteria. Mean time to CDMS by a second clinical attack was 11. 1 months compared to 19. 2 months by MRI lesions (P = 0. 03). None of the patients developed MS after 24 months of onset. All 17 patients who developed MS had positive CSF although 15 patients who had positive CSF did not develop MS during the 5 years of follow-up.ConclusionsThe majority of patients with ATM and normal brain MRI do not develop MS after 5 years of follow-up confirming the relatively low risk compared to patients with abnormal brain MRI scans. CSF is helpful in distinguishing patients more likely to develop MS. Compared to clinical attacks, serial imaging may not lead to an earlier diagnosis in ATM patients with normal brain MRI.

Effect of disease-modifying therapies on brain volume in relapsing-remitting multiple sclerosis: Results of a five-year brain MRI study

OBJECTIVE To compare the long-term effect of disease-modifying therapies (DMT) on brain volume loss in relapsing-remitting MS (RRMS) patients. METHODS We conducted a study to examine the effect of daily glatiramer acetate (GA), weekly low dose interferon beta (LD-IFNB), and high-dose high-frequency interferon beta disease (HD-IFNB) on brain volume loss over 5 years in RRMS patients. All patients were previously treatment naïve, had disease duration ≤5 years at the time of initiating DMT, and subsequently received the same DMT for 5 years continuously. The percentage change in brain volume (PCBV) was measured using fully automated software. MRI analysis was performed blinded to treatment allocation. RESULTS The adjusted PCBV from baseline to year 5 was -2.27% in GA, -2.62% in LD-IFNB, and -3.21% in the HD-IFNB groups (-2.27 vs -2.62, p=0.0036; -2.27 vs -3.21, p<0.0001; -2.62 vs -3.21, p<0.0001). These data remained unchanged from year 1 to year 5, after adjusting for pseudoatrophy in the first year. A group of RRMS patients that remained untreated for a period ranging from 8 to 24 months, served as controls. All treatment groups were significantly better than the rate of projected brain volume loss in the untreated group over 5 years (p<0.0001). CONCLUSIONS Global brain volume loss is a dynamic process even in relatively early RRMS patients that occurs despite intervention with therapy. However, all DMT significantly reduced the loss of brain volume compared to no treatment. The GA-treated group experienced the least reduction in brain volume over 5 years, compared to the LD-IFNB and HD-IFNB treated groups. These differences could be partly related to the immunologic consequences of GA therapy in RRMS.

Characterization of retinal architecture in Parkinson's disease.

BACKGROUND Parkinsons disease (PD) is a neurodegenerative disorder associated with dopaminergic cell loss and α-synuclein aggregation in Lewy bodies, which has been demonstrated in the retina. METHODS We performed a spectral-domain optical coherence tomography (OCT) study in patients with PD and healthy controls to measure the peripapillary retinal nerve fiber layer thickness and macular volume. Intra-retinal segmentation was performed to measure the volume of the retinal nerve fiber (RNFL), ganglion cell (GCL), inner plexiform (IPL), inner nuclear (INL), outer plexiform (OPL), and outer nuclear (ONL) layers. Analysis was carried out blinded to the clinical status of study participants. RESULTS 101 PD and 46 healthy control eyes were included in the study. In PD patients, peripapillary retinal nerve fiber layer was not significantly thinner (96.95 μm vs 94.42 μm, p=0.08) but macular volume was (8.58 mm3 vs 8.33 mm3, p=0.0002). Intra-retinal segmentation showed that PD subjects have reduced GCL, IPL, INL and ONL volumes. In contrast, the OPL volume was significantly increased (0.81 mm3 vs 0.78 mm3 p=0.0214). CONCLUSIONS Thickening of the OPL is a novel finding which may correspond to the localization of α-synuclein in the OPL of PD patients. We hypothesize that the enlargement of the OPL may represent a potential biomarker of α-synuclein aggregation in PD. This may have significant clinical implications.

Spinal cord atrophy in multiple sclerosis and relationship with disability across clinical phenotypes

BACKGROUND Several studies have shown a relationship between spinal cord atrophy and clinical disability in patients with multiple sclerosis (MS). OBJECTIVES We examined the correlation between cervical cord cross-sectional area at the C2 vertebral level (CSA-C2) and the expanded disability status scale (EDSS) in patients with relapsing-remitting and progressive forms of MS. The latter included both secondary and primary progressive MS patients. METHODS A total of 150 patients with MS were recruited from the Wayne State University MS clinic. Ninety-three had relapsing-remitting MS and 57 patients had progressive MS. MRI scan of the cervical cord was obtained for each patient. Correlation studies and multivariate regression analysis was performed, blinded to clinical status. RESULTS The mean age was 41.3 year old, 64.6% were women, mean disease duration was 11.2 years, CSA-C2 was 80.2mm(2) and mean EDSS was 3.8. There was significant correlation between CSA-C2 and EDSS (r -0.75, p<0.0001). Sub-group analysis showed CSA-C2 was 68.6mm(2) and 87.3mm(2) in the progressive and relapsing-remitting groups, respectively (p<0.0001). Multivariable regression showed that CSA-C2 was a significant predictor of disability independent of disease duration, and phenotype. CONCLUSIONS Our study demonstrates that CSA-C2 has a strong correlation with clinical disability in both RRMS and progressive MS. Greater spinal cord atrophy was seen in patients with progressive than relapsing-remitting MS. CSA-C2, disease duration, and phenotype are independent predictors of disability.

Longitudinal study of the substantia nigra in Parkinson disease: A high-field (1) H-MR spectroscopy imaging study.

The value of biomarkers in early diagnosis and development of therapeutics in Parkinsons disease (PD) is well established.

The Relationship Between Brain MR Spectroscopy and Disability in Multiple Sclerosis: 20-Year Data from the U.S. Glatiramer Acetate Extension Study

Conventional MRI techniques do not necessarily provide information about multiple sclerosis (MS) disease pathology or progression. Nonconventional MRI techniques, including proton magnetic resonance spectroscopy (1H‐MRS), are increasingly used to improve the qualitative and quantitative specificity of MR images. This study explores potential correlations between MRI measures of disease and disability progression as measured by the Expanded Disability Status Scale (EDSS), Functional Systems (FS), and ambulation index scores in a unique cohort of MS patients treated with glatiramer acetate that has been closely monitored for over 20 years.

Left ventricular dysfunction is associated with cerebral grey matter injury: an in-vivo brain MRI segmentation study.

BACKGROUND AND PURPOSE Patients with heart failure often experience cognitive deficits. The relationship between systolic function and cerebral gray matter injury is unclear. METHODS An automated program SIENAX (v2.2) was used to extract brain volume and for segmentation of grey and white matter in subjects with low left ventricular ejection fraction (< 50%) and normal ejection fraction (≥ 50%). T1-weighted spin-echo axial sequences were used for analysis. RESULTS 14 cases with low left ventricular ejection fraction and 14 age-matched controls were evaluated. A modest correlation between grey matter volume and low left ventricular ejection fraction was demonstrated (r=0.51, p=0.06), not seen with white matter volumes. The mean grey matter volume was 507.4±166.3 ml in the low left ventricular ejection fraction group and 541.3±167.2 ml in the control group (p=0.57). CONCLUSION Low left ventricular ejection fraction may lead to cerebral grey matter injury. Larger studies including multi-modal MRI and neuropsychological assessments are warranted to explore potential mechanisms.