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Since the G8 dementia summit in 2013, a number of initiatives have been established with the aim of facilitating the discovery of a disease-modifying treatment for dementia by 2025. This report is a summary of the findings and recommendations of a meeting titled "Tackling gaps in developing life-changing treatments for dementia", hosted by Alzheimer's Research UK in May 2018. The aim of the meeting was to identify, review, and highlight the areas in dementia research that are not currently being addressed by existing initiatives. It reflects the views of leading experts in the field of neurodegeneration research challenged with developing a strategic action plan to address these gaps and make recommendations on how to achieve the G8 dementia summit goals. The plan calls for significant advances in (1) translating newly identified genetic risk factors into a better understanding of the impacted biological processes; (2) enhanced understanding of selective neuronal resilience to inform novel drug targets; (3) facilitating robust and reproducible drug-target validation; (4) appropriate and evidence-based selection of appropriate subjects for proof-of-concept clinical trials; (5) improving approaches to assess drug-target engagement in humans; and (6) innovative approaches in conducting clinical trials if we are able to detect disease 10-15 years earlier than we currently do today.

There is growing interest in the development of novel approaches to secondary prevention trials in Alzheimer's disease to facilitate screening and recruitment of research participants and to reduce the time and costs associated with clinical trials. Several international research collaborations are setting up research infrastructures that link existing research cohorts, studies or patient registries to establish 'trial-ready' or 'readiness' cohorts. From these cohorts, individuals are recruited into clinical trial platforms. In setting up such research infrastructures, researchers must make ethically challenging design decisions in at least three areas: re-contacting participants in existing research studies, obtaining informed consent for participation in a readiness cohort, and disclosure of Alzheimer's disease-related biomarkers. These ethical considerations have been examined by a dedicated workgroup within the European Prevention of Alzheimer's Dementia (EPAD) project, a trans-European longitudinal cohort and adaptive proof-of-concept clinical trial platform. This paper offers recommendations for the ethical management of re-contact, informed consent and risk disclosure which may be of value to other research collaborations in the process of developing readiness cohorts for prevention trials in Alzheimer's disease and other disease areas., Competing Interests: LT is an employee of Janssen R and D LLC, EFPIA co-lead of the IMI-EPAD project and member of the Johnson and Johnson BioResearch Ethics Committee. MM is an employee of Novartis Pharma AG. The opinions expressed in this article are those of the authors and do not necessarily reflect the views of their employers or organizations. RM, EB, KT, SBe, SBa, DG, MS, CB and ER have no conflicts of interest with this paper.

Alzheimer's disease (AD) drug development is costly, time-consuming, and inefficient. Trial site functions, trial design, and patient recruitment for trials all require improvement. The Global Alzheimer Platform (GAP) was initiated in response to these challenges. Four GAP work streams evolved in the US to address different trial challenges: 1) registry-to-cohort web-based recruitment; 2) clinical trial site activation and site network construction (GAP-NET); 3) adaptive proof-of-concept clinical trial design; and 4) finance and fund raising. GAP-NET proposes to establish a standardized network of continuously funded trial sites that are highly qualified to perform trials (with established clinical, biomarker, imaging capability; certified raters; sophisticated management system. GAP-NET will conduct trials for academic and biopharma industry partners using standardized instrument versions and administration. Collaboration with the Innovative Medicines Initiative (IMI) European Prevention of Alzheimer's Disease (EPAD) program, the Canadian Consortium on Neurodegeneration in Aging (CCNA) and other similar international initiatives will allow conduct of global trials. GAP-NET aims to increase trial efficiency and quality, decrease trial redundancy, accelerate cohort development and trial recruitment, and decrease trial costs. The value proposition for sites includes stable funding and uniform training and trial execution; the value to trial sponsors is decreased trial costs, reduced time to execute trials, and enhanced data quality. The value for patients and society is the more rapid availability of new treatments for AD.

Alzheimer's dementia affects more than 40 million people worldwide with substantial increases in prevalence anticipated. Interventions that either modify risk or reduce the development of early disease could delay the onset of dementia or reduce the rate of cognitive and functional decline. The European Prevention of Alzheimer's Dementia (EPAD) is a public-private consortium, funded by the Innovative Medicines Initiative, designed to increase the likelihood of successful development of new treatments for the secondary prevention of Alzheimer's dementia. EPAD will help with testing of different agents in this pre-dementia population through four components: improvement of access to existing cohorts and registries, development of the EPAD Registry of approximately 24,000 people who might be at increased risk of developing Alzheimer's dementia, establishment of the EPAD Longitudinal Cohort Study of 6000 people at any one time, and establishment of an adaptive, proof-of-concept trial including 1500 participants at any given time. The need for EPAD and its key design elements are described, and we discuss EPAD in relation to similar projects in progress. These parallel efforts reflect the need for a coordinated, worldwide battle against dementia, in which EPAD will play a crucial role., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To assess the safety of galantamine in subjects with mild cognitive impairment (MCI), the ability of galantamine to benefit cognition and global functioning in subjects with MCI, and the ability of galantamine to delay conversion to dementia., Methods: In two studies, 2,048 subjects, 990 in Study 1 and 1,058 in Study 2, with a Clinical Dementia Rating (CDR) = 0.5, CDR memory score > or =0.5, without dementia were randomized to double-blind galantamine (16-24 mg/day) or placebo for 24 months. Primary efficacy endpoint at month 24 was number (%) of subjects who converted from MCI to dementia (CDR > or = 1.0)., Results: There were no differences between galantamine and placebo in 24-month conversion rates (Study 1: 22.9% [galantamine] vs 22.6% [placebo], p = 0.146; Study 2: 25.4% [galantamine] vs 31.2% [placebo], p = 0.619). Mean CDR-sum of boxes declined less with galantamine than placebo at 12 and 24 months in Study 1 (p = 0.024 [12 months] and p = 0.028 [24 months]), but not in Study 2 (p = 0.662 [12 months] and p = 0.056 [24 months]). Digit Symbol Substitution Test scores improved with galantamine in Study 1 at 12 months and in Study 2 at 24 months (Study 1: p = 0.009 [month 12] and p = 0.079 [Month 24]; Study 2: p = 0.154 [month 12] and p = 0.020 [month 24]). The most frequently reported adverse event was nausea (galantamine, 29%; placebo, 10%). Serious AEs occurred in 19% of each group. Mortality of the cohort after retrospectively determining the status of subjects (98.3%) at 24 months was 1.4% (galantamine) and 0.3% (placebo); RR (95% CI), 1.70 (1.00, 2.90)., Conclusions: Galantamine failed to significantly influence conversion to dementia. Galantamine was generally well tolerated. Whereas recorded mortality was greater in the galantamine group than in the placebo group in the original per-protocol assessment, a post hoc analysis of the cohort was consistent with no increased risk.

Objective: To assess the steady-state galantamine (GAL) bioavailability of the extended-release 24-mg qd capsule (GAL-ER) with and without food and to evaluate the relative bioavailability of GAL-ER with the immediate-release 12-mg bid tablet (GAL-IR) at steady state., Methods: This was a single-center, open-label, randomized, 3-way crossover study in 24 healthy volunteers (12 males and 12 females) aged 18 to 45 years. After 7 days of GAL-ER 8 mg qd each morning and 7 days of GAL-ER 16 mg qd each morning, subjects received the following treatments in randomized, crossover order (7 days each): GAL-ER 24 mg qd each morning (fasted before Day 7 morning dose), GAL-ER 24 mg qd each morning (fed before Day 7 morning dose), and GAL-IR 12 mg bid (fasted before Day 7). Pharmacokinetic parameters of GAL at steady state were determined after morning intake on Day 7 of each treatment week. Safety evaluations included adverse event (AE) reporting, physical examination, clinical laboratory tests, vital signs, and electrocardiography., Results: The treatment ratios of area under the plasma concentration-time curve of GAL from time 0-24 h post-dosing (AUC24 h), peak plasma concentration (Cmax), and pre-dose plasma concentration (Cmin) for GAL-ER fed/fasting were 105%, 112%, and 103%, respectively. The treatment ratios and 90% confidence intervals for all above mentioned pharmacokinetic parameters demonstrated bioequivalence (with the range of 80-125%), indicating that food had no effect on GAL-ER bioavailability. As anticipated, GAL-ER (fasting) had mean AUC24 h similar to GAL-IR (fasting), with lower Cmax (63 ng/mL vs 84 ng/mL) and longer time to reach Cmax (4.4 h vs 1.2 h). The treatment ratios and 90% confidence intervals for both AUC24 h and Cmin demonstrated bioequivalence (within the range of 80-125%). The treatment ratio for Cmax was 75.7%, indicating a 24% lower Cmax for GAL-ER than for GAL-IR. In this study, GAL-ER was safe and well tolerated with or without food and was comparable to the GAL-IR formulation., Conclusion: Food had no effect on the GAL bioavailability of GAL-ER at steady state. GAL-ER was bioequivalent to GAL-IR with respect to AUC24 h and Cmin.

The primary objective of this study was to evaluate the efficacy and tolerability of a flexible dosing regimen (16 or 24 mg/day) of galantamine prolonged-release capsule (PRC) compared with placebo in subjects with mild to moderate Alzheimer's disease (AD). This phase III, double-blind, placebo- and active-controlled, parallel-group trial randomized 971 patients to treatment for 6 months. Efficacy endpoints included change in the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog/11), Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC-plus), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), and Neuropsychiatric Inventory (NPI) scores. Galantamine was associated with significant improvements in the ADAS-cog/11 score but not in the CIBIC-plus or NPI scores. Galantamine PRC was associated with significant improvement in ADCS-ADL scores. Galantamine PRC had similar tolerability and safety profiles compared with twice-daily galantamine, and when administered as a once-daily flexible dosing regimen of 16 or 24 mg/day, was demonstrated to be as safe and effective for the treatment of mild to moderate AD., (Copyright (c) 2005 S. Karger AG, Basel.)

Mild cognitive impairment (MCI) often represents an early form of Alzheimer disease (AD). In both MCI and AD, characteristic cholinergic changes may occur. Functional magnetic resonance imaging (fMRI) may help to examine neurochemical changes in early disease by studying signal reactivity to pharmacological challenge. In this study, MCI patients [n=28; mean age 73.6+/-7.5; mini mental state examination (MMSE) 27.0+/-1.2] were scanned during task performance in a randomized trial under three different medication regimes: at baseline [BL; no galantamine (GAL)], after a single oral dose of GAL (SD), and after prolonged exposure (steady state: SS). Memory tasks included an episodic face-encoding task and a parametric n-letter back working memory (WM) task. Alterations in brain activation patterns before and after treatment were analyzed for both tasks using multilevel statistical analysis. Significant increases in brain activation from BL were observed after prolonged exposure only. For face encoding (n=28), these involved left prefrontal areas, the anterior cingulate gyrus, left occipital areas, and left posterior hippocampus. For working memory (n=28), increased activation was found in right precuneus and right middle frontal gyrus, coinciding with increased accuracy scores after GAL treatment. In conclusion, cholinergic challenge produces alterations in brain activation patterns in elderly MCI patients that can be detected with fMRI. This should encourage further functional imaging studies to examine the status of neurotransmitter systems in disease.

In clinical trials, short-term galantamine treatment produces consistent positive effects on global ratings, cognitive tests, and assessments of activities of daily living and behavior in patients with mild-to-moderate Alzheimer's disease (AD), providing the rationale for longer-term, open-label treatment. In this continuation trial following enrollment in previous 12-month trials, patients received galantamine 24 mg/day for a total of 24 months (total exposure up to 36 months). Primary efficacy measures were the ADAS-cog/11 and DAD. Adverse events (AEs) were coded to WHO preferred terms, including AEs begun in previous trials. Initial improvement in cognitive function was followed by a gradual decline, as measured by increased ADAS-cog/11 scores. At 36 months, ADAS-cog/11 scores increased by a mean (SEM) of 12.4 (0.80) points (P < 0.001) versus a projected 22-point increase for untreated patients. Functional abilities, as measured by the DAD, had decreased significantly at each time point versus baseline (P < 0.001). The most common treatment-emergent AEs were agitation (16.1%), insomnia (12.4%), fall (11.2%), and urinary tract infection (10.2%). AEs were mainly mild to moderate, appropriate for an elderly population, with few judged treatment related. Galantamine 24 mg/day is safe and effective for long-term treatment of mild-to-moderate AD. Potential exists for prolonged benefit with galantamine therapy versus lack of treatment for the long-term.

Background: Alzheimer disease (AD) causes progressive cognitive and functional decline over years. Although cholinesterase inhibitors have demonstrated efficacy in studies lasting 3 to 6 months, little is known about long-term therapy., Objective: To report the long-term cognitive effects of galantamine hydrobromide given continuously for 36 months in AD patients., Participants: Subjects were 194 US patients with mild to moderate AD who had been randomized to continuous galantamine therapy in either of 2 double-blind placebo-controlled trials. Subjects subsequently received open-label continuous galantamine therapy for up to 36 months., Main Outcome Measures: Effects on cognition were analyzed as change from study enrollment baseline in scores on the Alzheimer's Disease Assessment Scale-11-item cognitive subscale. Cognitive decline in galantamine-treated subjects was compared with that in a clinically similar historical control sample of AD patients who had received placebo for 12 months and with the mathematically predicted decline of untreated patients over 36 months. The rate of cognitive decline of patients who completed the entire 36-month trial (n = 119) was compared with that of patients who withdrew for any reason during the long-term open-label extension (n = 75). An inverted responder analysis was also performed in 36-month completers., Results: Patients treated continuously with galantamine for 36 months increased a mean +/- SE of 10.2 +/- 0.9 points on the Alzheimer's Disease Assessment Scale-11-item cognitive subscale-a substantially smaller cognitive decline (approximately 50%) than that predicted for untreated patients. Patients discontinuing galantamine therapy before 36 months had declined at a similar rate before discontinuation as those completing 36 months of treatment. Almost 80% of patients who received galantamine continuously for up to 36 months seemed to demonstrate cognitive benefits compared with those predicted for untreated patients., Conclusions: Cognitive decline over 36 months of continuous galantamine treatment was substantially less than the predicted cognitive decline of untreated patients with mild to moderate dementia. Thus, the cognitive benefits of galantamine seemed to be sustained for at least 36 months. These findings suggest that galantamine slows the clinical progression of AD.

Objective: To compare the long-term efficacy and safety of galantamine 24 mg/day and donepezil 10 mg/day in patients with Alzheimer's disease., Patients and Study Design: This was a rater-blinded, randomised, parallel-group multicentre study (18 outpatient clinics) in the UK. 182 patients (69 male, 113 female) with Alzheimer's disease were randomised to galantamine (n = 94) or donepezil (n = 88) for 52 weeks., Main Outcome Measures: The effects of galantamine and donepezil on function using the Bristol Activities of Daily Living Scale (BrADL); cognition using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog/11); behaviour using the Neuropsychiatric Inventory (NPI); caregiver burden using the Screen for Caregiver Burden; and safety were assessed., Results: BrADL total scores showed no significant difference between treatment groups in mean change from baseline to week 52. In the total population, in terms of cognition, galantamine patients' scores on the MMSE at week 52 did not differ significantly from baseline (-0.52 +/- 0.39, p < 0.5 vs baseline), whereas donepezil patients' scores deteriorated significantly from baseline (-1.58 +/- 0.42, p < 0.0005 vs baseline). The between-group difference in MMSE change, which showed a trend for superiority of galantamine, did not reach statistical significance (p < or = 0.1). In the ADAS-cog/11 analysis, between-group differences for the total population were not significant, whereas galantamine-treated patients with MMSE scores of 12-18 demonstrated an increase (worsening) in the ADAS-cog/11 score of 1.61 +/- 0.80 versus baseline, compared with an increase of 4.08 +/- 0.84 for patients treated with donepezil, with a significant between-group difference in favour of galantamine (p < or = 0.05). More caregivers of patients receiving galantamine reported reductions in burden compared with donepezil. Changes from baseline in NPI were similar for both treatments. Both treatments were well tolerated; most adverse events were transient and of mild-to-moderate intensity, and were consistent with the findings of previous clinical trials., Conclusions: Significant advantages were found in the treatment response to galantamine (versus donepezil) on cognition as measured by response rates on the MMSE and ADAS-cog/11.

The objective of this study was to compare the pharmacokinetics and safety of galantamine in subjects with hepatic impairment with those in healthy subjects. This was an open-label study in which a single oral 4-mg dose of galantamine was administered to volunteers with mild (Child-Pugh score of 5-6, n = 8), moderate (Child-Pugh score of 7-9, n = 8), or severe hepatic impairment (Child-Pugh score of 10-15, n = 1) and to healthy, matched control subjects (n = 8). Galantamine pharmacokinetics and safety (adverse events, laboratory test results, electrocardiograms, vital signs, and cardiac events) were assessed over 6 days after administration of galantamine. The pharmacokinetic parameters of galantamine were similar in subjects with mild hepatic impairment compared with healthy controls. Compared with the healthy control group, subjects with moderate hepatic impairment showed relative increases in the area under the plasma-concentration curve from zero to infinity (AUC0-infinity) (+33%) and terminal half-life (t1/2) (+30%) (p = 0.051 and p = 0.003, respectively), a 23% relative decrease in total plasma clearance (p = 0.061), and a small but significant relative increase in the fraction of free plasma galantamine (p = 0.009). Galantamine was well tolerated by all subjects. There were no serious adverse events (AEs) or premature withdrawals from the study because of AEs. Reported AEs were headache (three cases), nausea (one case), and paresthesia (one case). There were no clinically relevant changes in clinical laboratory findings, vital signs, and electrocardiograms. Low patient recruitment (n = 1) precluded statistical analysis of galantamine pharmacokinetics and safety in severe hepatic impairment. It was concluded that the pharmacokinetics of galantamine in subjects with mild hepatic impairment was similarto those in healthy subjects. In subjects with moderate hepatic impairment, galantamine clearance was decreased by approximately 23% compared with normal volunteers. Galantamine was also well tolerated and appeared to be safe in subjects with mild ormoderate hepatic impairment. Based on the study results, it appears that it would not be necessary to adjust doses of galantamine during administration to subjects with mild hepatic impairment. In subjects with moderately impaired hepatic function, dose titration should proceed cautiously. Unfortunately, difficulties with patient recruitment did not allow adequate assessment of the safety of galantamine in subjects with severe hepatic impairment in this study. Therefore, the use of galantamine in subjects with severe hepatic impairment is not recommended.

Objective: To assess the efficacy and safety of galantamine in Alzheimer's disease at 3 months using flexible dose escalation., Methods: A randomised, double blind, placebo controlled trial in 43 centres in the United States, Canada, Great Britain, South Africa, Australia, and New Zealand. Patients with probable Alzheimer's disease (n=386; 171 women) with a score of 11-24 on the mini mental state examination, and a score> or =12 on the cognitive subscale of the Alzheimer's disease assessment scale (ADAS-cog) were randomised to placebo, or galantamine escalated over 4 weeks to a maintenance dose of 24 or 32 mg/day. The primary outcome measures were the change in ADAS-cog score and the clinician's interview based impression of change plus caregiver input (CIBIC-plus) score. Activities of daily living (ADL) and behavioural symptoms were secondary outcomes. To compare the effects of highest levels of dosing, an observed cases (OC) analysis was undertaken, with classic intention to treat (ITT) and ITT with last observation carried forward (LOCF) as confirmatory analyses., Results: At 3 months, galantamine (24-32 mg/day) produced a significantly better outcome on cognitive function than placebo (treatment difference=1.9 points on ADAS-cog, p=0.002) and a significantly better global response than placebo, as measured by CIBIC-plus (deterioration in 21% of patients on galantamine v 37% on placebo; p<0.001). Galantamine produced significant benefits on basic and instrumental ADL. Behavioural symptoms did not change significantly from baseline levels in either group. Adverse events (primarily gastrointestinal) were of mild to moderate intensity. There were no important differences between the OC, ITT, and ITT/LOCF analyses. Most patients (82%) who were maintained on the higher dose of galantamine completed the study., Conclusions: Patients on galantamine, compared with those on placebo, experienced benefits in cognitive function and instrumental and basic activities of daily living. Flexible dose escalation of galantamine was well tolerated.

Objective: To evaluate whether degree of inflammatory activity in multiple sclerosis, expressed by frequency of gadolinium enhancement, has prognostic value for development of hypointense lesions on T1-weighted spin-echo magnetic resonance images, a putative marker of tissue destruction., Design: Cohort design with long-term follow-up. Thirty-eight patients with multiple sclerosis who in the past had been monitored with monthly gadolinium-enhanced magnetic resonance imaging for a median period of 10 months (range, 6-12 months) were reexamined after a median period of 40.5 months (range, 33-80 months)., Setting: Magnetic Resonance Center for Multiple Sclerosis Research, Amsterdam, the Netherlands, referral center., Main Outcome Measures: The new enhancing lesion rate (median number of gadolinium-enhancing lesions per monthly scan) during initial monthly follow-up; hypointense T1 and hyperintense T2 lesion load at first and last visit., Results: The number of enhancing lesions on entry scan correlated with the new enhancing lesions rate (r = 0.64; P<.001, Spearman rank correlation coefficient). The new enhancing lesion rate correlated with yearly increase in T1 (r = 0.42; P<.01, Spearman rank correlation coefficient) and T2 (r = 0.47; P<.01, Spearman rank correlation coefficient) lesion load. Initial T1 lesion load correlated more strongly with yearly increase in T1 lesion load (r = 0.68; P<.01, Spearman rank correlation coefficient)., Conclusions: Degree of inflammatory activity only partially predicted increase in T1 (and T2) lesion load at long-term follow-up. Initial T1 lesion load strongly contributed to subsequent increase in hypointense T1 lesion load, suggesting that there is a subpopulation of patients with multiple sclerosis who are prone to develop destructive lesions.

Multiple sclerosis (MS) is an immunologically mediated disorder in which inflammation and demyelination of the central nervous system white matter are prominent features, resulting in various neurological signs and symptoms. In most patients, the course of the disease is initially characterised by relapses and remissions. In patients with chronic disease there is a tendency towards a gradually progressive disease course. MS relapses can best be treated with a course of high dose intravenous methylprednisolone. In ambulatory patients with relapsing remitting MS, partial prevention of relapses can be achieved by the use of interferon-beta-1a or -1b, whereas there is (as yet less convincing) evidence that glatiramer acetate (copolymer-1) might also be effective. At this time, there is no proof that these drugs are effective in patients with progressive MS, although trial results are expected to be available soon. In patients with rapidly progressive disease, it might be worth considering the effect of methotrexate. Future treatment options include new strategies to interfere with disease-relevant, specific or nonspecific immune mechanisms as well as drugs that might promote remyelination. In spite of the advances that have been made over the past few years, symptomatic treatment, including a multidisciplinary rehabilitation approach, remains the mainstay of treatment of the majority of MS patients.

We present the case report of a 62 year-old female suffering from destructive rheumatoid arthritis (RA) for more than 20 years. She had complaints of progressive gait impairment and numbness in hands and feet. Neurological examination showed an unstable gait and pyramidal tract signs. Anterior atlantoaxial subluxation with pannus formation and cervical myelopathy were demonstrated using conventional X-ray studies and MRI. She was conservatively treated with a soft collar. Treatment with methotrexate and an intensive gait revalidation program were started. RA commonly involves the cervical spine, usually in advanced systemic disease after a mean delay of 16 years. Subluxations of the cervical spine are found in 43 to 86%, 50% of these patients are asymptomatic. The reported rate of neurological impairment due to cervical instability ranges from 7 to 58%. The three most common lesions resulting from cervical RA are atlantoaxial subluxation (50 to 70%), subaxial subluxation (15 to 25%) and cranial settling (20%). It is important to differentiate between cranial settling and atlantoaxial instability, as the latter may have a more benign history with less than 20% showing progressive instability. Cranial settling progresses in 35 to 50% of patients. The commonest presenting features of rheumatoid cervical myelopathy are isolated sensory symptoms. Most patients were found to have multiple neurological deficits once the myelopathy was diagnosed. A mean delay of 31 weeks between the first symptom and the diagnosis of the myelopathy is reported. The sensory symptoms are often misinterpreted as being due to entrapment neuropathy or rheumatoid peripheral neuropathy. Radiographic analysis indicates that the posterior atlantoodontoid interval (< or = 14 mm) is an important parameter that shows excellent correlation with the severity of paralysis.

Magnetic resonance imaging (MRI) provides a powerful tool for assessing disease activity in multiple sclerosis (MS), and its role as a surrogate marker for monitoring treatment efficacy is now becoming established. The most commonly used MRI parameters in treatment trials are (1) monthly gadolinium-enhanced MRI, with the number of active lesions serving as the outcome measure, and (2) annual lesion load quantification, in which change in MS lesion volume provides the MRI endpoint. We evaluated clinical/MRI correlations and the relationship between these two markers of disease activity in 73 patients with clinically definite MS. Quantification of T2 lesion load was performed at study entry and exit, with a median study duration of 11 months (range, 9 to 14 months). Monthly postgadolinium T1-weighted images were acquired between these time points. Lesion load at study entry was significantly correlated with the baseline Expanded Disability Status Scale (EDSS) score, but no significant longitudinal correlation was demonstrated. The number of enhancing lesions on the entry scan was predictive of subsequent relapse rate over the study duration and also correlated with the subsequent enhancing lesion activity over the study period. A significant correlation was found between change in lesion load and disease activity on the monthly scans. Our results suggest that annual lesion load quantification provides an efficient measure of ongoing disease activity, and this supports its application as a surrogate marker of disease evolution in phase III treatment trials.

Objectives: To calculate age adjusted risks for multiple sclerosis in relatives of Flemish patients with multiple sclerosis., Methods: Lifetime risks were calculated using the maximum likelihood approach., Results: Vital information was obtained on 674 probands with multiple sclerosis in Flanders and a total of their 26225 first, second, and third degree relatives. Full medical information to allow documentation of multiple sclerosis status was available for 21351 (81.4%) relatives. The age adjusted risk for parents was 1.61 (SEM 0.35)%, for siblings 2.10 (SE 0.36)%, and for children 1.71 (SEM 0.70)%. For aunts and uncles, the risk was 0.66 (SEM 0.13)%., Conclusions: The risk for first degree relatives of patients with multiple sclerosis in Flanders is increased 10-fold to 12-fold; for second degree relatives, it is increased threefold. This information can be used for risk counselling in families and provides additional support for the role of more than one locus contributing to the susceptibility of multiple sclerosis.

The purpose of this study was, first, to evaluate correlations between four potential magnetic resonance (MR) parameters for severe tissue destruction in multiple sclerosis (MS) lesions. Second, to evaluate the effect of incidental magnetization transfer (MT) effect on hypointense lesions in multislice T1 spin echo (SE) imaging. In 49 lesions, from 10 MS patients, MT ratio (MTR), T1 relaxation time, signal intensity (SI) on T1-weighted SE images normalized to normal-appearing white matter (NAWM), and SI normalized to cerebrospinal fluid (CSF) were measured. Differences in contrast of hypointense lesions were measured between single slice and multislice imaging. MTR correlated significantly (p < .001) with longitudinal relaxation rates (1/T1) (r = 0.84), SI normalized to NAWM (r = 0.78), and SI normalized to CSF (r = 0.75). The degree of reduction in contrast, caused by multislice imaging, correlated significantly with MTR of lesions (r = 0.60, p < .001), leading to reduction of hypointense lesion load (p < .01). We conclude that all four MR markers for severe tissue destruction are highly correlated when applied to selected hypointense lesions on T1-weighted SE images. Due to "incidental" off-resonance excitation, contrast and hypointense lesion load will be reduced in multislice T1-weighted SE images.

Inhomogeneous patient samples have been used in previous studies to determine the power of magnetic resonance imaging (MRI) for trial monitoring in multiple sclerosis (MS). These power-calculations might not be applicable to the active relapsing-remitting patient who is preferably included in trials. In order to reevaluate the power-calculations for MRI in the monitoring of treatment in strictly relapsing-remitting MS and to compare the power of different trial designs we studied 12 relapsing-remitting MS patients prospectively for a median period of 12 months using monthly clinical assessments and gadolinium-enhanced MRI. A median number of two clinical relapses/patient occurred of which a median of one was treated with steroids. A median of 1.59 new lesions/scan/patient was detected (range 0-8). The total number of new active lesions correlated significantly with study period relapses (SRCC = 0.72, P = 0.023). Computer simulations using the bootstrap technique yielded mostly lower power values for a parallel groups design than in previous studies except for short follow-periods in larger samples. In this-sample the open cross-over design was found to be between 20 and 40% more powerful. Results of power-calculations are clearly sample dependent implying that for treatment trial monitoring using MRI in relapsing-remitting MS conservative sample size estimates are to be used. In an active patient group open cross-over trial designs could be a very powerful alternative to parallel groups design.

There is evidence that treatment with an antibody to tumor necrosis factor alpha (TNF alpha) improves an animal model of multiple sclerosis (MS) and is beneficial in two systemic inflammatory disease in humans, but there are no reports about anti-TNF treatment of MS. Therefore, we treated two rapidly progressive MS patients with intravenous infusions of a humanized mouse monoclonal anti-TNF antibody (cA2) in an open-label phase I safety trial and monitored their clinical status, gadolinium-enhanced brain magnetic resonance imaging (MRI), and peripheral blood and cerebrospinal fluid (CSF) immunologic status. We did not notice any clinically significant neurologic changes in either patient. The number of gadolinium-enhancing lesions increased transiently after each treatment in both patients. CSF leukocyte counts and IgG index increased after each treatment. The transient increase in the number of gadolinium-enhancing lesions that followed each infusion of cA2 together with the increase in cells and immunoglobulin in the CSF of each patient suggest that the treatment caused immune activation and an increase in disease activity. These results suggest that further use of cA2 in MS is not warranted and that studies of other agents that antagonize TNF alpha should be carried out with frequent monitoring of gadolinium-enhanced MRIs.

MRI findings are increasingly used as outcome measures in therapeutic trials in MS. The discrepancy between the extent of the lesions on conventional T2 images and the clinical condition of the patient is one of the problems encountered in such studies. This clinical-radiological paradox prevents the use of MRI data as surrogate markers of disability in MS. A recent pilot study suggested a relationship between hypointense lesions on T1 MRI and disability. To assess in more detail the correlation of changes in hypointense lesion load on T1-weighted spin-echo MR images ("black holes") with changes in disability in MS, we studied 46 patients with clinically definite MS at baseline and after a median follow-up of 40 months. There was a significant correlation between baseline disability and hypointense lesion load (Spearman rank correlation coefficient [SRCC] = 0.46, p = 0.001). In secondary progressive patients, the rate of accumulation of these "black holes" was significantly related to progression rate (SRCC = 0.81, p < 0.0001). We speculate that the appearance of hypointense lesions is the MRI equivalent of a failure of remission. Overall, T1 lesion load measurements correlated better with clinical assessments than T2 lesion load measurements. Quantification of hypointense lesion load on T1-weighted spin-echo MRI helps to resolve the clinical-radiological paradox between disability and MRI and has the potential to be a surrogate marker of disability in MS.

In developed countries with a low incidence of tuberculosis, infection with Mycobacterium tuberculosis is easily overlooked as the cause of meningitis in an immunocompetent adult. Two cases are presented, with emphasis on the main reasons for delay of diagnosis. Neuroradiology revealed a progressive hypertrophic basal meningitis. The clinical and radiological outcome was good after tuberculostatic and corticosteroid treatment.

A case-control study of epilepsy in multiple sclerosis (MS) is presented using magnetic resonance (MR) imaging to semiquantitatively assess cortical-subcortical lesion load. In this sample of 13 pairs of cases with MS and epilepsy and controls with MS without epilepsy we found statistically higher cumulated cortical-subcortical lesion loads in the cases than in the controls (Wilcoxon, P = 0.036). Total lesion loads (cortical-subcortical plus deep white matter loads) did not differ significantly (P > 0.1) between cases and controls. The relative risk for seizures as determined by the odds ratio of a cortical-subcortical lesion load of > or = 20 was 8.8 (chi 2 = 5.23, P 0.025), the odds ratio of a large (> 1 cm) cortico-subcortical lesion was 4.7 (chi 2 = 4.9, P < 0.05), while the 2 MR criteria combined show an odds ratio of 19.2 (chi 2 = 8.0, P < 0.005). We conclude that: first, the presence of cortical-subcortical lesions in part accounts for the occurrence of seizures in MS patients; second, due to the substantial overlap of MR imaging scores between cases and controls the ultimate use of these MR imaging findings in the management of individual patients or in the organizations of trials should depend on the expected benefit of the treatment. If the benefit is only moderate or not known a cautious approach with exclusion of cases showing a substantial cortical-subcortical lesion load on MR imaging seems appropriate in trials with drugs, like 4-aminopyridine, that lower the epileptic threshold.

In a pilot trial, eight patients with multiple sclerosis were matched to control patients and received T-cell vaccination with irradiated T cells reactive to myelin basic protein (MBP) to deplete circulating MBP-reactive T cells. In the 2 years before and after vaccination, exacerbations decreased in five vaccinated patients (numbers 1, 2, 6-8) with relapsing-remitting disease from sixteen to three, respectively, and from twelve to ten in their matched controls. Magnetic resonance imaging showed a mean 8.0% increase in brain lesion size in the vaccinated patients compared with a 39.5% increase in the controls. Lesions and/or relapses worsened in three cases after vaccination in association with reappearance of circulating MBP-reactive T cells.

A growing amount of evidence suggests that a disturbance of immunological function is of importance in the pathogenesis of multiple sclerosis. This is reflected in the drugs used to slow progression and to treat relapses. Immunosuppressive drugs such as azathioprine, cyclophosphamide and cyclosporin might have some potential to slow down progression of multiple sclerosis, but their use is limited by potentially serious adverse effects. Recently, it was shown that interferon-beta-1b can diminish the exacerbation rate in multiple sclerosis without leading to unacceptable adverse effects. Nevertheless, symptomatic treatment remains of crucial importance in the management of multiple sclerosis patients. Spasticity, depression, fatigue and urinary, paroxysmal and sensory symptoms can all be alleviated to some extent with pharmacological interventions, although rehabilitation procedures and psychosocial consultations are no less important. Further therapeutic approaches to multiple sclerosis will be directed at either the specificity of the immune response or the grade of activation of the immune response. Magnetic resonance imaging techniques will play an important role in the evaluation of efficacy of new therapeutic agents.

Since its introduction in 1981 magnetic resonance imaging (MRI) has become the single most important paraclinical investigation in the diagnosis of multiple sclerosis (MS). Its sensitivity surpasses that of cerebrospinal fluid examination and trimodal evoked potentials. The clinical suspicion of multiple sclerosis remains mandatory because this greatly influences the specificity of MRI. Follow-up studies of MS patients using MRI with and without paramagnetic contrast enhancement have given us an insight in the 'realtime' dynamics of this disease which waxes and wanes for more than expected on clinical grounds alone. The impact of this 'subclinical' disease activity on the understanding of the disease and on the monitoring of therapeutical trials is discussed. The recently published European Community (EC) guidelines for the use of MRI in MS-related studies are the result of a major international effort to coordinate the multiple centers involved in MS related MRI research and should optimise multicentric (e.g. therapeutic trial) studies.

Background and Purpose: Dissecting aneurysms arising from the vertebrobasilar complex are rare and difficult to manage. More of their natural history needs to be known before treatment can be optimized., Case Description: We report a postpartum dissecting aneurysm of the right vertebrobasilar artery in a 31-year-old woman that was confirmed by angiographic identification of a double lumen. The intracranial segment of the right vertebral artery was thrombosed proximal to the aneurysm. The patient, managed conservatively, recovered well and, when reexamined 2 months later, was found to be neurologically intact. A repeat angiographic study at that time demonstrated that the aneurysm had resolved., Conclusions: Proximal occlusion may have protected the aneurysm from rupture and further dissection, thereby making surgery unnecessary.

The usefulness of non-contrast-enhanced, standardized magnetic resonance imaging for the longterm follow-up of MS patients was evaluated in a retrospective study in 36 patients with clinically definite MS. All had remitting-relapsing diseases courses. Sixteen patients remained clinically stable during follow-up. Mean duration of follow-up was 22 months (SD: 11). A mean number of 3 MRI examinations was performed in each of the patients (SD: 1). Subclinical evolution was detected in 56% of the stable patients, indicating that clinical data alone are insufficient to assess disease activity. The relapsing patients showed significantly more and larger changes on MRI than stable patients (P less than 0.001), indicating that MRI is well suited as a follow-up parameter in conjunction with clinical data. The time courses of these quantitative changes and of the qualitative changes of putative MS lesions on MRI are discussed. It is concluded that MRI is a good indicator of global disease activity in multiple sclerosis patients, which makes MRI very useful for the evaluation of therapeutic trials.