Joab Chapman

High b-Value q-Space Analyzed Diffusion-Weighted MRI: Application to Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) which affects nearly one million people worldwide, leading to a progressive decline of motor and sensory functions, and permanent disability. High b‐value diffusion‐weighted MR images (b of up to 14000 s/mm2) were acquired from the brains of controls and MS patients. These diffusion MR images, in which signal decay is not monoexponential, were analyzed using the q‐space approach that emphasizes the diffusion characteristics of the slow‐diffusing component. From this analysis, displacement and probability maps were constructed. The computed q‐space analyzed MR images that were compared with conventional T1, T2 (fluid attenuated inversion recovery (FLAIR)), and diffusion tensor imaging (DTI) images were found to be sensitive to the pathophysiological state of white matter. The indices used to construct this q‐space analyzed MR maps, provided a pronounced differentiation between normal tissue and tissues classified as MS plaques by the FLAIR images. More importantly, a pronounced differentiation was also observed between tissues classified by the FLAIR MR images as normal‐appearing white matter (NAWM) in the MS brains, which are known to be abnormal, and the respective control tissues. The potential diagnostic capacity of high b‐value diffusion q‐space analyzed MR images is discussed, and experimental data that explains the consequences of using the q‐space approach once the short pulse gradient approximation is violated are presented. Magn Reson Med 47:115–126, 2002.

APOE genotype is a major predictor of long-term progression of disability in MS

To the Editor: In a recent article, Chapman et al.1 described a statistical association of the APOE genotype with long-term progression of disability in MS. They showed that the APOE-ε4 allele was not associated with higher risk of developing MS, but was associated with accumulation of disability (p 0.002); other studies have shown an association between MS disease activity and APOE-ε4 as well. It has been shown recently that genetic loci for autoimmune/inflammatory disorders tend to cluster or colocalize throughout the genome,2-5 suggesting, in some cases, common or shared loci involving underlying immune regulatory pathways. The overlap of inflammatory loci is particularly true on chromosome 19q13 at the point containing the APOE gene. The table shows polymorphic markers linked to autoimmune/inflammatory diseases that are identical, overlap, or are within 10 centimorgans of the APOE locus that has been associated with MS progression of disability. A number of candidate loci for susceptibility to infectious organisms have been mapped to this point as well (data not shown). These human diseases shown here include MS, celiac disease, asthma, type I diabetes, and systemic lupus erythematosus—all of which involve progressive disability brought on by chronic, immune-mediated tissue damage. Similarly, AD has been linked and associated with APOE-ε4 and is thought to have an inflammatory component. Overlap of multiple loci from multiple diseases to the point containing the APOE gene could occur for a number of reasons. These reasons could include coincidental associations, statistical artifacts, or biological artifacts due to gene and chromosome structural organization. One possible biological interpretation of multiple clinically related diseases mapping to identical or overlapping genetic intervals is that the contribution of the APOE genotype may not be disease specific, but may predispose to a basic component of the inflammatory response, which manifests itself in different immune-mediated diseases with an inflammatory component.

Antiphospholipid antibodies permeabilize and depolarize brain synaptoneurosomes

Antiphospholipid antibodies (aPL) are associated with neurological diseases such as stroke, migraine, epilepsy and dementia and are thus associated with both vascular and non-vascular neurological disease. We have therefore examined the possibility that these antibodies interact directly with neuronal tissue by studying the electrophysiological effects of aPL on a brain synaptosoneurosome preparation. IgG from patients with high levels of aPL and neurological involvement was purified by protein-G affinity chromatography as was control IgG pooled from ten sera with low levels of aPL. Synaptoneurosomes were purified from perfused rat brain stem. IgG from the patient with the highest level of aPL at a concentration equivalent to 1:5 serum dilution caused significant depolarization of the synaptoneurosomes as determined by accumulation of the lipophylic cation [3H]-tetraphenylphosphonium. IgG from this patient as well as IgG from two elderly patients with high levels of aPL were subsequently shown to permeabilize the synaptosomes to labeled nicotinamide adenine dinucleotide (NAD) and pertussis toxin-ADP-ribose transferase (PTX-A protein) as assayed by labeled ADP-ribosylation of G-proteins in the membranes. No such effects were seen with the control IgG. aPL may thus have the potential to disrupt neuronal function by direct action on nerve terminals. These results may explain some of the non-thromboembolic CNS manifestations of the antiphospholipid syndrome.

ACE, MTHFR, Factor V Leiden, and APOE Polymorphisms in Patients With Vascular and Alzheimer’s Dementia

BACKGROUND AND PURPOSE There is a growing interest in the use of genetic markers in the differential diagnosis of dementia. In the current study we examined the usefulness of genetic risk factors for vascular disease as markers for vascular dementia (VD). METHODS The groups included 41 patients with VD, 49 patients with dementia of the Alzheimers type, and 40 age-matched control subjects without dementia. These patients were genotyped for vascular disease-associated polymorphisms in the genes coding for methylenetetrahydrofolate reductase (MTHFR), angiotensin-converting enzyme (ACE), factor V Leiden (FVL), and a common genetic risk factor for AD, apolipoprotein E epsilon4 (APOE epsilon4). RESULTS There was no significant association between ACE, MTHFR, and FVL genotypes with VD whether compared with subjects with AD or with control subjects. There was a higher frequency of APOE epsilon4 alleles in patients with AD (30%, P=0.016) and VD (26%, P=0.07) compared with control subjects (15%). CONCLUSIONS VD is not associated with the genetic risk factors for vascular disease examined in this study, indicating that the pathogenesis of VD may differ from other vascular diseases.

Creutzfeldt-Jacob disease associated with the PRNP codon 200LYS mutation: An analysis of 45 families

Abstract200Lys mutation in the human PRNP coding region has been identified in 45 of the 55 CJ-Daffected families thus far presented to our NIH laboratory. These codon 200lys families have a total of 87 patients, and originate from 7 different countries: Slovakia, Poland, Germany, Tunisia, Greece, Libya, and Chile. Forty-seven patients were neuropathologically verified, and brain tissue from 14 patients transmitted disease to experimental primates.The mutation was found by direct sequencing in 4 patients, and it was detected by restriction endonuclease analysis with BsmA 1 and/or the single nucleotide extension reaction in 36 other patients and 45 of 109 first degree relatives (1 parent, 14 siblings, and 30 children).The mutation is associated with all known geographical clusters of CJD (Slovakia, Libyan Jews, Chile) in which the annual mortality rate is tens or hundreds of times higher than the world average of 1 per million. All patients originating from the cluster areas carried the mutation, but it was seen in only 1 of 103 unrelated control individuals from the same areas, and in none of 102 controls from other areas, indicating a strong association between the mutation and disease. The penetrance of the mutation was estimated to be 0.56.Branches of some families migrating from cluster areas to other countries continue to have CJD over several generations, suggesting that CJD in these families is a genetic disorder, in which the 200Lys mutation is responsible for the disease.

Persistence on therapy and propensity matched outcome comparison of two subcutaneous interferon beta 1a dosages for multiple sclerosis

Objectives To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics. Methods Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded. Results Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as “lack of efficacy” (3.3% vs. 1.7%), “scheduled stop” (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages. Conclusions Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from “real-world” database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry.

Neuronal-binding antibodies from patients with antiphospholipid syndrome induce cognitive deficits following intrathecal passive transfer

Antiphospholipid antibodies (aPL) have been suggested to play a role in causing cognitive and behavioral impairments. In the present study we investigated the pathogenic potential of aPL by intracerebro-ventricular (ICV) administration of immunoglobulins (IgG) from patients with antiphospholipid syndrome (APS). IgG, purified from the sera of four APS patients, was tested for binding to normal mouse brain by immunohistological staining. These IgG (7.5 m g) were injected ICV unilaterally to male C3H mice. Mice injected with IgG purified from pooled sera derived from healthy subjects served as controls. The mice were examined neurologically for motor function and coordination, and cognitively in a Morris water maze. The cognitive tests were performed with the experimenterblinded to the treatment. The performance of the mice in four separate experiments was compared by analysis of variance with repeated measures. IgG from one APS patient was found to bind best to neuronal structures in the hippocampus and cerebral cortex. Mice (n 43) injected with this IgG performed worse in the water maze compared to the controls(n 45) with significant effects of the aPL IgG on the overall performance of the mice (treatment, P < 0.03), on learning throughout the experiment (treatment ×day, P < 0.02) and on short term memory (treatment ×day ×trial, P < 0.002). IgG injected from two of the three other patients also bound specifically to mouse brain neurons and produced an impairment in performance of the water maze. These results support the hypothesis that aPL that gain access to the central nervous system may play a direct role in the pathogenesis of neurological manifestations of APS.

MSBase: an international, online registry and platform for collaborative outcomes research in multiple sclerosis

Observational cohort studies are a powerful tool to assess the long-term outcome in chronic diseases. This study design has been utilized in local and regional outcome studies in multiple sclerosis (MS) and has yielded invaluable epidemiological information. The World Wide Web now provides an excellent opportunity for an international, collaborative cohort study of MS outcomes. A web platform-MSBase-has been designed to collect prospective data on patients with MS. It is purely observational, enabling participating neurologists to contribute data on diagnosis, treatment and progress, to review anonymous aggregate data and to benchmark their patient population against other patient subsets or the entire dataset. MSBase facilitates collaborative research by allowing the online creation of investigator-initiated regional, national and international substudies. The registry aims to answer epidemiological questions that can only be addressed by prospective assessments of large patient cohorts. The registry is funded through the independent MSBase Foundation, and governed by an International Scientific Advisory Board. The MSBase Foundation commenced operations in July 2004 and since then, 22 neurologists from 11 countries have joined MSBase and are contributing 2400 patients to the total data pool.

Head circumference and incident Alzheimer’s disease Modification by apolipoprotein E

Background: The clinical expression of AD likely occurs when the accumulation of degeneration in specific brain regions leads to the descent below a critical threshold of “brain reserve” beyond which normal cognitive function cannot be maintained. The association between head circumference (HC), a measure of brain reserve, and the incidence of probable AD was examined in a large nondemented cohort that has been followed since 1992 and its modification by APOE ε4 genotype. Methods: Fifty-nine incident cases of probable AD were identified from 1,869 initially nondemented individuals seen at the baseline examination (1992 to 1994) and followed for a mean of 3.8 years. Variables measured at baseline included age, education, gender, HC, height, weight, and score on the National Adult Reading Test–Revised. APOE was genotyped at the time of the first biennial examination (1994 to 1996) and was available for 1,111 individuals in the cohort. Cox proportional hazard regression was performed to estimate hazard ratios (HR) for probable AD for HC and other covariates. Results: Incident cases were significantly older, less educated, shorter, and lighter, had lower estimated verbal IQ scores, and were more likely to have at least one APOE ε4 allele than unaffected individuals. The HR associated with the lowest tertile of HC (<21.4 inches) adjusted for education, gender, and APOE ε4 was 2.3 (95% CI 0.7 to 6.9, p = 0.16). The HR for one or two APOE ε4 alleles was significant (HR = 4.8, 95% CI 1.8 to 12.9, p = 0.002). The combination of low HC and APOE ε4 strongly predicted earlier onset of AD with HR = 14.1 (95% CI 3.0 to 65, p = 0.0007). Conclusions: Smaller HC, in the presence of the APOE ε4 allele, hastens the age at onset of AD. These results support the brain reserve hypothesis and its importance in precipitating the clinical expression of AD among genetically predisposed individuals.

Non-stroke neurological syndromes associated with antiphospholipid antibodies: Evaluation of clinical and experimental studies

Although many types of neurological disorders and events have been described in association with antiphospholipidantibodies(aPL) and the antiphospholipidsyndrome (APS), only ischaemic stroke is reasonably well established and accepted as a diagnostic criterion for the syndrome. We propose to evaluate, classify and rank the association of other neurological manifestations as possible, probable, or definite according to the data available from clinical studies and animal models. By these criteria, none of the neurologicaldisordersor events such as epilepsy, psychiatricdisease, dementia, transverse myelitis, multiple sclerosis-like disease, chorea, migraine, Guillian-Barrèsyndrome, and sensory-neural hearing loss, can be definitely associated with aPL or APS.