Does Gadolinium Deposition Lead to Metabolite Alteration in the Dentate Nucleus? An MRS Study in Patients with MS.

BACKGROUND AND PURPOSE: Repeat contrast-enhanced MR imaging exposes patients with relapsing-remitting MS to frequent administration of gadolinium-based contrast agents. We aimed to investigate the potential metabolite and neurochemical alterations of visible gadolinium deposition on unenhanced T1WI in the dentate nucleus using MRS. MATERIALS AND METHODS: This prospective study was conducted in a referral university hospital from January 2020 to July 2021. The inclusion criteria for case and control groups were as follows: 1) case: patients with relapsing-remitting MS, visible gadolinium deposition in the dentate nucleus (ribbon sign), >5 contrast-enhanced MR images obtained; 2) control 1: patients with relapsing-remitting MS without visible gadolinium deposition in the dentate nucleus, >5 contrast-enhanced MR images obtained; 3) control 2: patients with relapsing-remitting MS without visible gadolinium deposition in the dentate nucleus, <5 contrast-enhanced-MR images obtained; and 4) control 3: adult healthy individuals, with no contrast-enhanced MR imaging. Dentate nucleus and pontine single-voxel 12 × 12 × 12 MRS were analyzed using short TEs. RESULTS: Forty participants (10 per group; 27 [67.5%] female; mean age, 35.6 [SD, 9.6] years) were enrolled. We did not detect any significant alteration in the levels of NAA and choline between the studied groups. The mean concentrations of mIns were 2.7 (SD, 0.73) (case), 1.5 (SD, 0.8) (control 1), 2.4 (SD, 1.2) (control 2), and 1.7 (SD, 1.2) (control 3) (P = .04). The mean concentration of Cr and mIns (P = .04) and the relative metabolic concentration (dentate nucleus/pons) of lipid 1.3/Cr (P = .04) were significantly higher in the case-group than in healthy individuals (controls 1-3). Further analyses compared the case group with cumulative control 1 and 2 groups and showed a significant increase in lactate (P = .02), lactate/Cr (P = .04), and Cr (dentate nucleus/pons) (P = .03) in the case group. CONCLUSIONS: Although elevated concentrations of Cr, lactate, mIns, and lipid in the dentate nucleus of the case group indicate a metabolic disturbance, NAA and choline levels were normal, implying no definite neuronal damage.

Quantification of diagnostic biomarkers to detect multiple sclerosis lesions employing (1)H-MRSI at 3T.

Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) enables the quantification of metabolite concentration ratios in the brain. The major purpose of the current work is to characterize NAA/Cho, NAA/Cr and Myo/Cr in multiple sclerosis (MS) patients, and to estimate their reproducibility in healthy controls. Twelve MS patients and five healthy volunteers were imaged using (1)H-MRSI at 3T. Eddy current correction was performed using a single-voxel non-water suppressed acquisition on an external water phantom. Time-domain quantification was carried out using subtract-QUEST technique, and based on an optimal simulated metabolite database. Reproducibility was evaluated on the same quantified ratios in five normal subjects. An optimal database was created for the quantification of the MRSI data, consisting of choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), lactate (Lac), lipids, myo-inositol (Myo) and glutamine + glutamate (Glx). Decreasing of NAA/Cr and NAA/Cho ratios, as well as an increase in Myo/Cr ratio were observed for MS patients in comparison with control group. Reproducibility of NAA/Cr, NAA/Cho and Myo/Cr in control group was 0.98, 0.87 and 0.64, respectively, expressed as the squared correlation coefficient R (2) between duplicate experiments. We showed that MRSI alongside the time-domain quantification of spectral ratios offers a sensitive and reproducible framework to differentiate MS patients from normals.

Emerging tumefactive MS after switching therapy from interferon-beta to fingolimod: A case report.

We describe a case of tumefactive multiple sclerosis, based on characteristic imaging features and excluding alternative diagnoses, presented with relapse 18 weeks after switching betaferon to fingolimod. Recent reported cases of this paradoxical demyelinating reaction in a setting of fingolimod-related immune system alterations seem to be something more than an accidental event. Immune cell shifting underlying a genetic susceptibility factor has been suggested to participate in this disastrous adverse effect. It could be a warning sign which physicians should take it into account for better recognition of patients at risk and select candidates for this management.

Serum and CSF PDGF-AA and FGF-2 in relapsing-remitting multiple sclerosis: a case-control study.

BACKGROUND AND PURPOSE: Fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor-A (PDGF-AA) are potent modulators of oligodendrocytes, the main responsible cells for myelin regeneration. We measured FGF-2 and PDGF-AA in the sera and cerebrospinal fluid (CSF) of patients with relapsing-remitting multiple sclerosis (RR-MS) and compared these values with control subjects. METHODS: Twenty-three patients with RR-MS and 23 subjects without inflammatory and demyelinating diseases were included. Serum samples of the patients were collected in both relapse and remission phases and were analyzed with ELISA method. CSF was drawn during the relapse period. Blood and CSF were drawn from control subjects for comparison. Wilcoxon and Mann-Whitney U-test and Spearman's rank correlation were used for analysis. P values of <0.05 were considered significant. RESULTS: Age and sex distribution were similar in both groups. Serum values of FGF-2 were higher in relapse phase compared with remission phase, with a trend toward significance (P=0.052). CSF PDGF-AA showed significant negative correlation with disease duration (correlation coefficient=-0.58, P=0.004). Serum levels of PDGF did not differ between two phases significantly. There was no difference in serum and CSF values of these factors between patients and controls. When we compared patients with prolonged disease with controls, a significant difference between the CSF levels of PDGF-AA was observed (mean±SEM 2.78±0.8 in controls vs. 0.55±0.29 in patients with MS≥2 years, P<0.05). CONCLUSION: Our study was the first to show that CSF PDGF-AA is related to disease duration. Supporting previous findings we showed that serum and CSF levels of these factors are weak indicators of disease severity.

Pharmacogenetic Study on the Effect of Rivastigmine on PS2 and APOE Genes in Iranian Alzheimer Patients.

BACKGROUND/AIMS: Alzheimer disease (AD) is a complex and genetically heterogeneous disorder, and certain genes such as PS2 and APOE4 contribute to the development of AD. Due to its heterogeneity, AD-predisposing genes could vary in different populations. Moreover, not all AD patients will respond to the same therapy. We specifically investigated the effect ofrivastigmine (Exelon) on PS2 and APOE genes in Iranian AD patients. METHODS: A total of 100 AD patients, 67 patients with sporadic AD (SAD) and 33 patients with familial AD (FAD), receiving rivastigmine therapy and 100 healthy controls were studied. PCR-RFLP was used for genotyping of PS2 and APOE. RESULTS: We found a positive association between the PS2 -A allele and SAD patients (p(c) = 0.01), and the PS2 +A/-A genotype was significantly more frequent in SAD than FAD patients (p(c) = 0.009). The APOE4 allele was associated with total AD, SAD and FAD (p(c) = 0.000002). Patients with the PS2 +A/-A genotype and bigenic genotypes of +A/-A·∊3/∊3 and +A/-A·∊3/∊4 were the best responders to Exelon therapy, and those with the PS2 +A/+A and APOE ∊3/∊4 genotypes were the worst responders. CONCLUSION: Our findings suggest that the PS2 and APOE4 alleles and genotypes affect both AD risk and response to rivastigmine therapy.

Sympathetic skin response (SSR) in multiple sclerosis and clinically isolated syndrome: a case-control study.

OBJECTIVE: To compare the sympathetic skin responses (SSRs) in patients with multiple sclerosis (MS), clinically isolated syndrome (CIS), and healthy controls. METHODS: SSR was recorded on both hands and feet in 30 patients and 20 healthy controls. SSR results (latency measurements) were compared in patients with normal or abnormal brainstem auditory evoked potentials (BAEPs), visual evoked potentials (VEPs) and somatosensory evoked potentials (SEPs). RESULTS: Twenty-three (76.6%) and sixteen patients (53.3%) with MS had abnormal SSR recordings based on 2-standard deviation (SD) or 3-SD (from the mean of the control group) abnormality criteria, respectively. Sixty-six percent and 40 percent of patients had abnormal (>2SD) SSR in at least one hand and one foot, respectively. Patients with absent SSR had more severe disease and higher Expanded Disability Status Scale (EDSS) scores. Fourteen patients had an EDSS of zero, of whom nine had abnormal SSR and others had at least one abnormal EP study. Patients with abnormal SSR had significantly more abnormal BAEPs and SEPs than patients with normal SSR. SSR latencies were significantly correlated with EDSS and disease duration (P<0.01). All patients had at least one abnormal electrophysiological study. ROC-curve analysis showed that a cut-off score of 7008 ms as the sum of all-4-limb SSR latencies had a 80% sensitivity and 95% specificity for differentiating MS patients from healthy controls. CONCLUSIONS: This study suggests that SSR is a useful tool for assessment of autonomic function and can be complementary to EDSS and other electrophysiological studies in patients with MS and CIS.

Lafora disease: a case report, pathologic and genetic study.

A 19-year-old male patient presented with progressive myoclonic seizures and speech disorder. The patient had photosensitivity, a few episodes of sudden transient blindness, and infrequent complex visual auras, dysarthria and mild ataxia, frequent myoclonic jerks prominently in the legs and severe dementia. Microscopic examination of the axillary skin biopsy revealed periodic acid-Schiff positive inclusion bodies in abluminal side of the apocrine sweat gland acini. Molecular screening showed a homozygous R241X mutation in EPM2A. Genotyping helps in the correct diagnosis of the Lafora disease (LD), which may be difficult to diagnose based on the available histopathological testing only. Our study is an effort to determine the distribution of mutations in LD patients in our region.

Saffron in the treatment of patients with mild to moderate Alzheimer's disease: a 16-week, randomized and placebo-controlled trial.

WHAT IS KNOWN: Herbal medicines have been used in the treatment of behavioural and psychological symptoms of dementia but with variable response. Crocus sativus (saffron) may inhibit the aggregation and deposition of amyloid ß in the human brain and may therefore be useful in Alzheimer's disease (AD). OBJECTIVE: The goal of this study was to assess the efficacy of saffron in the treatment of mild to moderate AD. METHODS: Forty-six patients with probable AD were screened for a 16-week, double-blind study of parallel groups of patients with mild to moderate AD. The psychometric measures, which included AD assessment scale-cognitive subscale (ADAS-cog), and clinical dementia rating scale-sums of boxes, were performed to monitor the global cognitive and clinical profiles of the patients. Patients were randomly assigned to receive capsule saffron 30 mg/day (15 mg twice per day) (Group A) or capsule placebo (two capsules per day) for a 16-week study. RESULTS: After 16 weeks, saffron produced a significantly better outcome on cognitive function than placebo (ADAS-cog: F=4·12, d.f.=1, P=0·04; CDR: F=4·12, d.f.=1, P=0·04). There were no significant differences in the two groups in terms of observed adverse events. WHAT IS NEW AND CONCLUSION: This double-blind, placebo-controlled study suggests that at least in the short-term, saffron is both safe and effective in mild to moderate AD. Larger confirmatory randomized controlled trials are called for.