NEWS FROM THE WORLD- Association of Bone Mineral Density With the Risk of Intracranial Aneurysm

Abstract

Importance  Disruption of extracellular matrix integrity is critically involved in both intracranial aneurysm and bone fragility. Furthermore, both intracranial aneurysm and osteoporosis have a female predominance, and sex hormones are considered to affect this discrepancy.

Objective  To evaluate the association between bone mineral density and intracranial aneurysm.

Design, Setting, and Participants  A cross-sectional study conducted with 14 328 patients who underwent brain magnetic resonance angiography and bone mineral densitometry as a part of a health examination at a specialized center for comprehensive health examination in Seoul, the largest metropolitan area in the Republic of Korea, between December 2004 and November 2015. After excluding patients with insufficient clinical information (n = 1102) and with ambiguous intracranial arterial lesion (n = 441), 12 785 were included in the analysis.

Exposures  Bone mineral density was measured at the lumbar vertebrae (L1 to L4), femur neck, and total hip using dual-energy x-ray absorptiometry.

Main Outcomes and Measures  Multiple logistic regression or linear regression was used to examine the association between tertiles of bone mineral density and the presence, size, and multiplicity of intracranial aneurysms. In secondary analyses, we analyzed postmenopausal women and men 50 years and older (n = 8722) because they are particularly at risk of decreased bone mineral density.

Results  Among 12 785 patients in the study (7242 women [56.6%]; mean [SD] age, 54.8 [10.1] years) intracranial aneurysms were found in 472 patients (3.7%). Lower bone mineral density was associated with an increased risk of harboring intracranial aneurysm. In multivariable logistic regression analyses, odds ratios for the highest compared with the lowest bone mineral density tertile were 1.30 (95% CI, 1.03-1.64) in the lumbar spine, 1.30 (95% CI, 1.03-1.64) in the femoral neck, and 1.27 (95% CI, 1.01-1.60) in the total hip after adjusting for age, sex, and vascular risk factors. In a linear regression model adjusted for age, sex, and vascular risk factors, the lowest tertile of bone mineral density in the lumbar spine was associated with an increased log-transformed size of aneurysm (β, 0.196; SE, 0.047). In secondary analyses, these associations were more definite and a low T score (<−1 SD) was additionally associated with multiple aneurysms (OR, 1.84; 95% CI, 1.05-3.30) after adjusting for age, sex, and vascular risk factors.

Conclusions and Relevance  Bone mineral density may be associated with the presence, size, and multiplicity of intracranial aneurysm. The study findings provide evidence for shared pathophysiology between intracranial aneurysm and bone fragility.

JAMA Neurology 2017

NEWS FROM THE WORLD- Interpreting Biomarker Results in Individual Patients With Mild Cognitive Impairment in the Alzheimer’s Biomarkers in Daily Practice (ABIDE) Project

Abstract

Importance  Biomarkers do not determine conversion to Alzheimer disease (AD) perfectly, and criteria do not specify how to take patient characteristics into account. Consequently, biomarker use may be challenging for clinicians, especially in patients with mild cognitive impairment (MCI).

Objective  To construct biomarker-based prognostic models that enable determination of future AD dementia in patients with MCI.

Design, Setting, and Participants  This study is part of the Alzheimer’s Biomarkers in Daily Practice (ABIDE) project. A total of 525 patients with MCI from the Amsterdam Dementia Cohort (longitudinal cohort, tertiary referral center) were studied. All patients had their baseline visit to a memory clinic from September 1, 1997, through August 31, 2014. Prognostic models were constructed by Cox proportional hazards regression with patient characteristics (age, sex, and Mini-Mental State Examination [MMSE] score), magnetic resonance imaging (MRI) biomarkers (hippocampal volume, normalized whole-brain volume), cerebrospinal fluid (CSF) biomarkers (amyloid-β1-42, tau), and combined biomarkers. Data were analyzed from November 1, 2015, to October 1, 2016.

Main Outcomes and Measures  Clinical end points were AD dementia and any type of dementia after 1 and 3 years.

Results  Of the 525 patients, 210 (40.0%) were female, and the mean (SD) age was 67.3 (8.4) years. On the basis of age, sex, and MMSE score only, the 3-year progression risk to AD dementia ranged from 26% (95% CI, 19%-34%) in younger men with MMSE scores of 29 to 76% (95% CI, 65%-84%) in older women with MMSE scores of 24 (1-year risk: 6% [95% CI, 4%-9%] to 24% [95% CI, 18%-32%]). Three- and 1-year progression risks were 86% (95% CI, 71%-95%) and 27% (95% CI, 17%-41%) when MRI results were abnormal, 82% (95% CI, 73%-89%) and 26% (95% CI, 20%-33%) when CSF test results were abnormal, and 89% (95% CI, 79%-95%) and 26% (95% CI, 18%-36%) when the results of both tests were abnormal. Conversely, 3- and 1-year progression risks were 18% (95% CI, 13%-27%) and 3% (95% CI, 2%-5%) after normal MRI results, 6% (95% CI, 3%-9%) and 1% (95% CI, 0.5%-2%) after normal CSF test results, and 4% (95% CI, 2%-7%) and 0.5% (95% CI, 0.2%-1%) after combined normal MRI and CSF test results. The prognostic value of models determining any type of dementia were in the same order of magnitude although somewhat lower. External validation in Alzheimer’s Disease Neuroimaging Initiative 2 showed that our models were highly robust.

Conclusions and Relevance  This study provides biomarker-based prognostic models that may help determine AD dementia and any type of dementia in patients with MCI at the individual level. This finding supports clinical decision making and application of biomarkers in daily practice.

Introduction

Alzheimer disease (AD) has a long predementia phase that is often referred to as mild cognitive impairment (MCI). The cumulative progression incidence from MCI to dementia is approximately 50% over 3 years.^1,2 This finding simultaneously implies that the other half of patients with MCI will remain clinically stable or return to a normal state. Therefore, there is an urgent need for individualized risk assessments in patients with MCI.³

Identification of abnormal biomarkers in patients with MCI helps to identify individuals at high risk of progression to AD dementia.⁴ Atrophy on brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) concentrations of amyloid-β1-42 (Aβ1-42) and tau protein are among the most widely used AD biomarkers and are associated with an increased risk of AD dementia at follow-up.^5- 10 These findings resulted in the National Institute on Aging and Alzheimer Association (NIA-AA) criteria, stating that biomarker evidence enhances the pathologic specificity of the diagnosis of AD dementia and MCI due to AD dementia, facilitating an accurate and early diagnosis.^3,11,12 However, these criteria do not specify how to deal with conflicting or borderline biomarker results and how to take patient characteristics into account. Moreover, although MRI and CSF are increasingly used in clinical practice, their diagnostic and prognostic value is not perfect. Therefore, optimal use of these biomarkers in daily clinical practice is challenging.^3,13 We aimed to construct prognostic models based on MRI measures and CSF biomarkers for patients with MCI, taking into account patient characteristics to obtain individualized probabilities of progression.

JAMA Neurology 2017

NEWS FROM THE WORLD- Clustering of Neuropsychiatric Disease in First-Degree and Second-Degree Relatives of

Importance  Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition primarily involving the motor system. There is increasing epidemiologic evidence of an association between ALS and a wider spectrum of neurodegenerative and neuropsychiatric disorders among family members, including schizophrenia and psychotic illness and suicidal behavior.

Objective  To examine the frequency and range of neuropsychiatric conditions that occur within individual first-degree and second-degree relatives of patients with ALS.

Design, Setting, and Participants  In this population-based, case-control family aggregation study, all 202 patients included in the Irish ALS Register between January 1, 2012, and January 31, 2014, with definite, probable, or possible ALS as defined by El Escorial criteria were invited to participate. A total of 75 patients were unable or refused to participate and were excluded; the remaining 127 patients with incident ALS were genotyped for the C9orf72 repeat expansion and 132 age- and sex-matched controls were included in the study.

Main Outcome and Measures  The prevalence of defined neuropsychiatric disease in first-degree and second-degree relatives of patients with ALS and matched controls was determined.

Results  Mean (SD) age at diagnosis of the 127 patients in the study (58 women and 69 men) was 64.2 (10.7) years. Data from 2116 relatives of patients with ALS were reported, including 924 first-degree relatives, 1128 second-degree relatives, and 64 third-degree relatives. Data from controls were reported from 829 first-degree and 1310 second-degree relatives. A total of 77 patients with ALS (61.4%) and 51 control participants (38.6%) reported at least 1 first-degree or second-degree relative with a history of schizophrenia, psychosis, suicide, depression, alcoholism, or autism (relative risk [RR], 1.50; 95% CI, 1.08-2.17; P = .02). Cluster analysis suggested the following 2 subgroups based on the number of family members with a neuropsychiatric condition: expected (0-2) and high (≥3). Within the high subgroup, ALS kindreds presented a significantly higher rate of psychiatric illness than did controls (28 of 39 [71.8%]; mean [SD] number of siblings, 4.29 [1.41]; P = .001). A strong family history of schizophrenia (RR, 3.40; 95% CI, 1.27-9.30; P = .02), suicide (RR, 3.30; 95% CI, 1.07-10.05; P = .04), autism (RR, 10.10; 95% CI, 1.30-78.80; P = .03), and alcoholism (RR, 1.48; 95% CI, 1.01-2.17; P = .045) was reported in ALS kindreds. A total of 5 of 29 probands (17.2%) with a strong family history of neuropsychiatric conditions (≥3 first-degree or second-degree relatives) carried the C9orf72 repeat expansion.

Conclusions and Relevance  Neuropsychiatric symptoms in addition to schizophrenia, including obsessive-compulsive disorder, autism, and alcoholism, occur more frequently in ALS kindreds than in controls. The presence of the C9orf72 repeat expansion does not fully account for this finding, suggesting the presence of additional pleiotropic genes associated with both ALS and neuropsychiatric disease in the Irish population.

JAMA Neurology 2017

NEWS FROM THE WORLD- Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Summary

Background

Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial.

Methods

We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II–IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229.

Findings

Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference −11·7, 95% CI −24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy.

Interpretation

The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed.

Lancet Neurology 2017

NEWS FROM THE WORLD-Beta burst dynamics in Parkinson’s disease OFF and ON dopaminergic medication

Abstract

Exaggerated basal ganglia beta activity (13–35 Hz) is commonly found in patients with Parkinson’s disease and can be suppressed by dopaminergic medication, with the degree of suppression being correlated with the improvement in motor symptoms. Importantly, beta activity is not continuously elevated, but fluctuates to give beta bursts. The percentage number of longer beta bursts in a given interval is positively correlated with clinical impairment in Parkinson’s disease patients. Here we determine whether the characteristics of beta bursts are dependent on dopaminergic state. Local field potentials were recorded from the subthalamic nucleus of eight Parkinson’s disease patients during temporary lead externalization during surgery for deep brain stimulation. The recordings took place with the patient quietly seated following overnight withdrawal of levodopa and after administration of levodopa. Beta bursts were defined by applying a common amplitude threshold and burst characteristics were compared between the two drug conditions. The amplitude of beta bursts, indicative of the degree of local neural synchronization, progressively increased with burst duration. Treatment with levodopa limited this evolution leading to a relative increase of shorter, lower amplitude bursts. Synchronization, however, was not limited to local neural populations during bursts, but also, when such bursts were cotemporaneous across the hemispheres, was evidenced by bilateral phase synchronization. The probability of beta bursts and the proportion of cotemporaneous bursts were reduced by levodopa. The percentage number of longer beta bursts in a given interval was positively related to motor impairment, while the opposite was true for the percentage number of short duration beta bursts. Importantly, the decrease in burst duration was also correlated with the motor improvement. In conclusion, we demonstrate that long duration beta bursts are associated with an increase in local and interhemispheric synchronization. This may compromise information coding capacity and thereby motor processing. Dopaminergic activity limits this uncontrolled beta synchronization by terminating long duration beta bursts, with positive consequences on network state and motor symptoms.

Brain 2017

NEWS FROM THE WORLD- Serum neurofilament light is sensitive to active cerebral small vessel disease

ABSTRACT

Objective: To explore whether serum neurofilament light chain protein (NfL) levels are increased in patients with MRI-confirmed recent small subcortical infarcts (RSSI) compared to healthy controls and to determine the subsequent course and determinants of NfL levels in a longitudinal manner.

Methods: In a prospectively collected group of symptomatic patients with an RSSI (n = 79, mean age 61 ± 11 years, 67% male), we analyzed brain MRI and serum NfL using a Single Molecule Array (Simoa) assay at baseline and at 3 and 15 months after stroke. Community-dwelling healthy age- and sex-matched individuals with comparable severity of MRI white matter hyperintensities (WMH) (n = 53) served as controls.

Results: Patients with an RSSI had higher NfL baseline levels compared to controls (73.45 vs 34.59 pg/mL, p < 0.0001), and they were increasingly higher with the time from stroke symptom onset to blood sampling (median 4 days, range 1–11 days, r_s = 0.51, p < 0.0001). NfL levels remained increased at the 3-month follow-up but returned to normal at 15 months after stroke. NfL levels were associated with RSSI size and baseline WMH severity and were especially high in patients with new, clinically silent cerebral small vessel disease (CSVD)–related lesions at follow-up.

Conclusions: Serum NfL is increased in patients with an RSSI and the occurrence of new CSVD-related MRI lesions, even when clinically silent. This suggests NfL as a blood biomarker for active CSVD.

Neurology 2017

NEWS FROM THE WORLD- Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine

ABSTRACT

Objective: To determine outcomes among patients with migraine in the emergency department (ED) who receive IV hydromorphone vs IV prochlorperazine + diphenhydramine.

Methods: This study was conducted in 2 EDs in New York City. Patients who met international criteria for migraine were eligible for participation if they had not used an opioid within the previous month. Clinicians, participants, investigators, and research personnel were blinded to treatment. Patients were randomized in blocks of 4. Participants received hydromorphone 1 mg or prochlorperazine 10 mg + diphenhydramine 25 mg. Diphenhydramine was administered to prevent akathisia, a common side effect of IV prochlorperazine. The primary outcome was sustained headache relief, defined as achieving a headache level of mild or none within 2 hours of medication administration and maintaining that level for 48 hours without the requirement of rescue medication. A planned interim analysis was conducted once 48-hour data were available for 120 patients.

Results: The trial was halted by the data monitoring committee after 127 patients had been enrolled. The primary outcome was achieved in the prochlorperazine arm by 37 of 62 (60%) participants and in the hydromorphone arm by 20 of 64 (31%) participants (difference 28%, 95% confidence interval 12–45, number needed to treat 4, 95% confidence interval 2–9).

Conclusions: IV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the ED and should not be used as first-line therapy.

ClinicalTrials.gov identifier: NCT02389829.

Classification of evidence: This study provides Class I evidence that for patients in the ED with migraine, IV prochlorperazine + diphenhydramine is superior to IV hydromorphone.

Neurology 2017