Showing papers in "JAMA Neurology in 2018"

The Parkinson Pandemic-A Call to Action

Abstract: Pandemics are usually equated with infectious diseases such as Zika, influenza, and HIV. However, an imminent noninfectious pandemic, Parkinson disease (PD), requires immediate action. Neurological disorders are now the leading cause of disability in the world.1 Among these neurological disorders, the fastest growing is PD, whose growth is surpassing that of Alzheimer disease.1 From 1990 to 2015, the prevalence of, and thus disability and deaths owing to, PD more than doubled.1 The Global Burden of Disease Study estimates that 6.2 million individuals currently have PD. Because the incidence of PD increases sharply with age and because the world’s population is aging, the number of individuals affected is poised for exponential growth (Figure). Conservatively applying worldwide prevalence data from a 2014 meta-analysis2 to projections of the world’s future population,3 the number of people with PD will double from 6.9 million in 2015 to 14.2 million in 2040. Applying this same growth rate to the lower estimate by the Global Burden of Disease study (6.2 million in 2015) projects to a staggering 12.9 million affected by 2040. All these estimates likely understate the true prevalence of PD. The future burden will probably be higher owing to underreporting (record-based studies miss many who have not been diagnosed), declining smoking rates (smoking is associated with a 50% decreased risk of PD), and increasing longevity. Regardless of the exact numbers, if PD were an infectious condition, it would rightly be called a pandemic.4 To address this pandemic, the PD community should follow the efforts of the HIV community as detailed in David France’s book How to Survive a Plague.5 In just 15 years, the affected community took what was initially an unknown and rapidly fatal illness and transformed it into one that was highly treatable, allowing millions of individuals around the world to live long, healthy lives. France outlines at least 4 efforts that should be applied to PD.

Current Concepts in Diagnosis and Treatment of Functional Neurological Disorders.

Abstract: Importance: Functional neurological disorders (FND) are common sources of disability in medicine. Patients have often been misdiagnosed, correctly diagnosed after lengthy delays, and/or subjected to poorly delivered diagnoses that prevent diagnostic understanding and lead to inappropriate treatments, iatrogenic harm, unnecessary and costly evaluations, and poor outcomes. Observations: Functional Neurological Symptom Disorder/Conversion Disorder was adopted by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, replacing the term psychogenic with functional and removing the criterion of psychological stress as a prerequisite for FND. A diagnosis can now be made in an inclusionary manner by identifying neurological signs that are specific to FNDs without reliance on presence or absence of psychological stressors or suggestive historical clues. The new model highlights a wider range of past sensitizing events, such as physical trauma, medical illness, or physiological/psychophysiological events. In this model, strong ideas and expectations about these events correlate with abnormal predictions of sensory data and body-focused attention. Neurobiological abnormalities include hypoactivation of the supplementary motor area and relative disconnection with areas that select or inhibit movements and are associated with a sense of agency. Promising evidence has accumulated for the benefit of specific physical rehabilitation and psychological interventions alone or in combination, but clinical trial evidence remains limited. Conclusions and Relevance: Functional neurological disorders are a neglected but potentially reversible source of disability. Further research is needed to determine the dose and duration of various interventions, the value of combination treatments and multidisciplinary therapy, and the therapeutic modality best suited for each patient.

Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial.

Abstract: Importance Migraine is a disabling neurological disease characterized by severe headache attacks. Treatment options reduce migraine frequency for many patients, but adverse effects lead to discontinuation in many patients. Objective To demonstrate that galcanezumab is superior to placebo in the prevention of episodic migraine with or without aura. Design, Setting, and Participants The EVOLVE-1 (Evaluation of LY2951742 in the Prevention of Episodic Migraine 1) trial was a double-blind, randomized, placebo-controlled (January 11, 2016, to March 22, 2017) trial comparing galcanezumab (120 mg and 240 mg) vs placebo. Patients received treatments once monthly for 6 months (subcutaneous injection via prefilled syringe) and were followed up for 5 months after their last injection. It was a multicenter, clinic-based study involving 90 sites in North America. Participants in the study were adults (aged 18 to 65 years) with at least a 1-year history of migraine, 4 to 14 migraine headache days per month and a mean of at least 2 migraine attacks per month within the past 3 months, and were diagnosed prior to age 50 years. During the study, no other preventive medications were allowed. A total of 1671 patients were assessed; 809 did not meet study entry or baseline criteria, and 858 were included in the intent-to-treat population. Interventions Patients were randomized (2:1:1) to monthly placebo, galcanezumab, 120 mg, and galcanezumab, 240 mg. Main Outcomes and Measures The primary outcome was overall mean change from baseline in the number of monthly migraine headache days during the treatment period. Secondary measures included at least 50%, at least 75%, and 100% reduction in monthly migraine headache days, migraine headache days with acute medication use, and scores from the Migraine-Specific Quality of Life questionnaire, Patient Global Impression of Severity, and Migraine Disability Assessment. Treatment-emergent adverse events and serious adverse events were reported. Results Of the 1671 patients assessed, 858 (mean age, 40.7 years; 718 women [83.7%]) met study entry criteria and received at least 1 dose of investigational product. The primary objective was met for both galcanezumab doses; treatment with galcanezumab significantly reduced monthly migraine headache days (bothP Conclusions and Relevance Galcanezumab 120-mg and 240-mg monthly injections provided clinical benefits and improved functioning. The incidence rate of adverse events was low, demonstrating the favorable tolerability profile of galcanezumab. Trial Registration ClinicalTrials.gov Identifier:NCT02614183

Disease Course and Treatment Responses in Children With Relapsing Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease

Abstract: Importance Myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) are consistently identified in a range of demyelinating disorders in adults and children. Current therapeutic strategies are largely center specific, and no treatments have been formally evaluated. Objective To examine the clinical phenotypes, treatment responses, and outcomes of children with relapsing MOG-Ab–associated disease. Design, Setting, and Participants This study prospectively collected demographic, clinical, and radiologic data from 102 patients from 8 countries of the EU Paediatric Demyelinating Disease Consortium from January 1, 2014, through December 31, 2016. Patients were treated according to local protocols. Main Outcomes and Measures Annualized relapse rates (ARRs) and Expanded Disability Status Scale (EDSS) scores before and during treatment with disease-modifying drugs (DMDs). Results A total of 102 children were identified (median [range] age, 7.0 [1.5-7.9] years; male to female ratio, 1.0:1.8; white to other race/ethnicity ratio, 3.6:1.0). Original diagnoses were neuromyelitis optica spectrum disorder (44 patients [43.1%]), acute disseminated encephalomyelitis followed by optic neuritis (20 [19.6%]), multiphasic disseminated encephalomyelitis (20 [19.6%]), and relapsing optic neuritis (18 [17.6%]). In all, 464 demyelinating events were reported. Treated patients had more relapses (median, 3.0; range, 1.0-17.0) than untreated patients (median, 1.0; range 1.0-7.0) (P = .009) and higher EDSS scores (median, 1.5; interquartile range, 0-2.5) than untreated patients (median, 1.0; interquartile range, 0-1.5) (P Conclusions and Relevance Although commonly used to treat patients with multiple sclerosis, DMDs were not associated with clinical improvement in children with MOG-Ab–associated disease, whereas azathioprine, mycophenolate mofetil, rituximab, and particularly intravenous immunoglobulins were associated with a reduction in relapse frequency. A correct diagnosis of relapsing MOG-Ab–associated disorders is therefore important to optimize immune treatment.

Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic Imaging.

Abstract: Importance Synaptic loss is well established as the major structural correlate of cognitive impairment in Alzheimer disease (AD). The ability to measure synaptic density in vivo could accelerate the development of disease-modifying treatments for AD. Synaptic vesicle glycoprotein 2A is an essential vesicle membrane protein expressed in virtually all synapses and could serve as a suitable target for synaptic density. Objective To compare hippocampal synaptic vesicle glycoprotein 2A (SV2A) binding in participants with AD and cognitively normal participants using positron emission tomographic (PET) imaging. Design, Setting, and Participants This cross-sectional study recruited 10 participants with AD and 11 participants who were cognitively normal between November 2015 and June 2017. We hypothesized a reduction in hippocampal SV2A binding in AD, based on the early degeneration of entorhinal cortical cell projections to the hippocampus (via the perforant path) and hippocampal SV2A reductions that had been observed in postmortem studies. Participants underwent high-resolution PET scanning with ((R)-1-((3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), a compound more commonly known as11C-UCB-J, for SV2A. They also underwent high-resolution PET scanning with carbon 11–labeled Pittsburgh Compound B (11C-PiB) for β-amyloid, magnetic resonance imaging, and cognitive and neurologic evaluation. Main Outcomes and Measures Outcomes were11C-UCB-J–specific binding (binding potential [BPND]) via PET imaging in brain regions of interest in participants with AD and participants who were cognitively normal. Results Ten participants with AD (5 male and 5 female; mean [SD] age, 72.7 [6.3] years; 10 [100%] β-amyloid positive) were compared with 11 participants who were cognitively normal (5 male and 6 female; mean [SD] age, 72.9 [8.7] years; 11 [100%] β-amyloid negative). Participants with AD spanned the disease stages from amnestic mild cognitive impairment (n = 5) to mild dementia (n = 5). Participants with AD had significant reduction in hippocampal SV2A specific binding (41%) compared with cognitively normal participants, as assessed by11C-UCB-J–PETBPND(cognitively normal participants: mean [SD]BPND, 1.47 [0.37]; participants with AD: 0.87 [0.50];P = .005). These reductions remained significant after correction for atrophy (ie, partial volume correction; participants who were cognitively normal: mean [SD], 2.71 [0.46]; participants with AD: 2.15 [0.55];P = .02). Hippocampal SV2A-specific bindingBPNDwas correlated with a composite episodic memory score in the overall sample (R = 0.56;P = .01). Conclusions and Relevance To our knowledge, this is the first study to investigate synaptic density in vivo in AD using11C-UCB-J–PET imaging. This approach may provide a direct measure of synaptic density, and it therefore holds promise as an in vivo biomarker for AD and as an outcome measure for trials of disease-modifying therapies, particularly those targeted at the preservation and restoration of synapses.

Development of a New Classification System for Idiopathic Inflammatory Myopathies Based on Clinical Manifestations and Myositis-Specific Autoantibodies

Abstract: Importance Idiopathic inflammatory myopathies are heterogeneous in their pathophysiologic features and prognosis. The emergence of myositis-specific autoantibodies suggests that subgroups of patients exist. Objective To develop a new classification scheme for idiopathic inflammatory myopathies based on phenotypic, biological, and immunologic criteria. Design, Setting, and Participants An observational, retrospective cohort study was performed using a database of the French myositis network. Patients identified from referral centers for neuromuscular diseases were included from January 1, 2003, to February 1, 2016. Of 445 initial patients, 185 patients were excluded and 260 adult patients with myositis who had complete data and defined historical classifications for polymyositis, dermatomyositis, and inclusion body myositis were enrolled. All patients were tested for anti–histidyl-ARN-t- synthetase (Jo1), anti–threonine-ARN-t-synthetase (PL7), anti–alanine-ARN-t-synthetase (PL12), anti–complex nucleosome remodeling histone deacetylase (Mi2), anti-Ku, anti–polymyositis/systemic scleroderma (PMScl), anti–topoisomerase 1 (Scl70), and anti–signal recognition particle (SRP) antibodies. A total of 708 variables were collected per patient (eg, cancer, lung involvement, and myositis-specific antibodies). Main Outcomes and Measures Unsupervised multiple correspondence analysis and hierarchical clustering analysis to aggregate patients in subgroups. Results Among 260 participants (163 [62.7%] women; mean age, 59.7 years; median age [range], 61.5 years [48-71 years]), 4 clusters of patients emerged. Cluster 1 (n = 77) included patients who were male, white, and older than 60 years and had finger flexor and quadriceps weakness and findings of vacuolated fibers and mitochondrial abnormalities. Cluster 1 regrouped patients who had inclusion body myositis (72 of 77 patients [93.5%]; 95% CI, 85.5%-97.8%;P Conclusions and Relevance These findings suggest a classification of idiopathic inflammatory myopathies with 4 subgroups: dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome. This classification system suggests that a targeted clinical-serologic approach for identifying idiopathic inflammatory myopathies may be warranted.

Using Smartphones and Machine Learning to Quantify Parkinson Disease Severity: The Mobile Parkinson Disease Score

Abstract: Importance Current Parkinson disease (PD) measures are subjective, rater-dependent, and assessed in clinic. Smartphones can measure PD features, yet no smartphone-derived rating score exists to assess motor symptom severity in real-world settings. Objectives To develop an objective measure of PD severity and test construct validity by evaluating the ability of the measure to capture intraday symptom fluctuations, correlate with current standard PD outcome measures, and respond to dopaminergic therapy. Design, Setting, and Participants This observational study assessed individuals with PD who remotely completed 5 tasks (voice, finger tapping, gait, balance, and reaction time) on the smartphone application. We used a novel machine-learning–based approach to generate a mobile Parkinson disease score (mPDS) that objectively weighs features derived from each smartphone activity (eg, stride length from the gait activity) and is scaled from 0 to 100 (where higher scores indicate greater severity). Individuals with and without PD additionally completed standard in-person assessments of PD with smartphone assessments during a period of 6 months. Main Outcomes and Measures Ability of the mPDS to detect intraday symptom fluctuations, the correlation between the mPDS and standard measures, and the ability of the mPDS to respond to dopaminergic medication. Results The mPDS was derived from 6148 smartphone activity assessments from 129 individuals (mean [SD] age, 58.7 [8.6] years; 56 [43.4%] women). Gait features contributed most to the total mPDS (33.4%). In addition, 23 individuals with PD (mean [SD] age, 64.6 [11.5] years; 11 [48%] women) and 17 without PD (mean [SD] age 54.2 [16.5] years; 12 [71%] women) completed in-clinic assessments. The mPDS detected symptom fluctuations with a mean (SD) intraday change of 13.9 (10.3) points on a scale of 0 to 100. The measure correlated well with the Movement Disorder Society Unified Parkinson Disease’s Rating Scale total (r = 0.81;P Conclusions and Relevance Using a novel machine-learning approach, we created and demonstrated construct validity of an objective PD severity score derived from smartphone assessments. This score complements standard PD measures by providing frequent, objective, real-world assessments that could enhance clinical care and evaluation of novel therapeutics.

Effect of General Anesthesia and Conscious Sedation During Endovascular Therapy on Infarct Growth and Clinical Outcomes in Acute Ischemic Stroke: A Randomized Clinical Trial.

Abstract: Importance Endovascular therapy (EVT) is the standard of care for select patients who had a stroke caused by a large vessel occlusion in the anterior circulation, but there is uncertainty regarding the optimal anesthetic approach during EVT. Observational studies suggest that general anesthesia (GA) is associated with worse outcomes compared with conscious sedation (CS). Objective To examine the effect of type of anesthesia during EVT on infarct growth and clinical outcome. Design, Setting, and Participants The General or Local Anesthesia in Intra Arterial Therapy (GOLIATH) trial was a single-center prospective, randomized, open-label, blinded end-point evaluation that enrolled patients from March 12, 2015, to February 2, 2017. Although the trial screened 1501 patients, it included 128 consecutive patients with acute ischemic stroke caused by large vessel occlusions in the anterior circulation within 6 hours of onset; 1372 patients who did not fulfill inclusion criteria and 1 who did not provide consent were excluded. Primary analysis was unadjusted and according to the intention-to-treat principle. Interventions Patients were randomized to either the GA group or the CS group (1:1 allocation) before EVT. Main Outcomes and Measures The primary end point was infarct growth between magnetic resonance imaging scans performed before EVT and 48 to 72 hours after EVT. The hypothesis formulated before data collection was that patients who were under CS would have less infarct growth. Results Of 128 patients included in the trial, 65 were randomized to GA, and 63 were randomized to CS. For the entire cohort, the mean (SD) age was 71.4 (11.4) years, and 62 (48.4%) were women. Baseline demographic and clinical variables were balanced between the GA and CS treatment arms. The median National Institutes of Health Stroke Scale score was 18 (interquartile range [IQR], 14-21). Four patients (6.3%) in the CS group were converted to the GA group. Successful reperfusion was significantly higher in the GA arm than in the CS arm (76.9% vs 60.3%;P = .04). The difference in the volume of infarct growth among patients treated under GA or CS did not reach statistical significance (median [IQR] growth, 8.2 [2.2-38.6] mL vs 19.4 [2.4-79.0] mL;P = .10). There were better clinical outcomes in the GA group, with an odds ratio for a shift to a lower modified Rankin Scale score of 1.91 (95% CI, 1.03-3.56). Conclusions and Relevance For patients who underwent thrombectomy for acute ischemic stroke caused by large vessel occlusions in the anterior circulation, GA did not result in worse tissue or clinical outcomes compared with CS. Trial Registration clinicaltrials.gov Identifier:NCT02317237

Association of MOG-IgG Serostatus With Relapse After Acute Disseminated Encephalomyelitis and Proposed Diagnostic Criteria for MOG-IgG–Associated Disorders

Abstract: Importance Recent studies have reported a higher relapse rate following an initial inflammatory demyelinating disorder in pediatric patients with persistent seropositivity of antibodies targeting myelin oligodendrocyte glycoprotein (MOG-IgG1). To date, the clinical implications of longitudinal MOG-IgG1 seropositivity using live cell assays with IgG1 secondary antibodies in adults after acute disseminated encephalomyelitis (ADEM) are unknown. Objective To determine whether MOG-IgG1 serostatus (transient vs persistent) and titer change over time provide clinical utility in predicting the likelihood of relapse after ADEM. Design, Setting, and Participants This cohort study identified patients with an initial diagnosis of ADEM evaluated at a single referral center between January 1, 1990, and October 1, 2017. Fifty-one patients were included, including 31 children and 20 adults. Longitudinal serologic testing was performed detecting autoantibodies targeting aquaporin 4 (AQP4-IgG) and MOG-IgG1 with clinically validated fluorescence-activated cell sorting assays. Patients were divided into 3 cohorts: persistent seropositivity, transient seropositivity, and seronegativity. Main Outcomes and Measures Clinical demographic characteristics, longitudinal AQP4-IgG and MOG-IgG1 serostatus, titers, relapses, use of immunotherapy, and Expanded Disability Status Scale score at follow-up. Results Of 51 patients presenting with an initial diagnosis of ADEM, 20 (39%) were adult, 24 (47%) were female, and ages ranged from 12 months to 57 years. Seventeen patients fulfilled criteria for persistent seropositivity; of those, 8 of 9 children (89%) and 7 of 8 adults (88%) had at least 1 relapse after median (range) follow-up periods of 75 (15-236) months and 39 (9-161) months, respectively. Eight patients (16%), including 4 adults, fulfilled criteria for transient seropositivity; of those, no children and 1 of 4 adults (25%) relapsed after median (range) follow-up periods of 32 (24-114) months and 16 (13-27) months, respectively. Of 24 patients with AQP4-IgG and MOG-IgG seronegativity, 6 of 17 children (35%) and 2 of 7 adults (29%) had at least 1 relapse after median (range) follow-up periods of 36 (3-203) months and 34 (15-217) months, respectively. There were only 2 patients, including 1 adult, with AQP4-IgG seropositivity, and both relapsed. The hazard ratio for relapses in those with persistent MOG-IgG1 positivity compared with AQP4-IgG and MOG-IgG1 seronegativity was 3.1 (95% CI, 1.1-8.9; P = .04) in children and 5.5 (95% CI, 1.4-22.5; P = .02) in adults. Immunotherapy was used in 5 of 9 children (56%) and 6 of 8 adults (75%) with persistent seropositivity and in 3 of 17 children (18%) and 1 of 7 adults (14%) with AQP4-IgG and MOG-IgG seronegativity. Conclusions and Relevance Relapse occurred in 15 of 17 patients (88%) with persistent MOG-IgG1 seropositivity after ADEM; only 1 patient with transient seropositivity experienced relapse. Our data extend the clinical utility of MOG-IgG1 serological testing to adult patients and highlights that longitudinal serologic evaluation of MOG-IgG1 could help predict disease course and consideration of immunotherapy.

Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease

Abstract: Importance Circadian rhythm disturbances occur in symptomatic Alzheimer disease (AD) and have been hypothesized to contribute to disease pathogenesis. However, it is unknown whether circadian changes occur during the presymptomatic phase of the disease. Objective To examine the associations between circadian function, aging, and preclinical AD pathology in cognitively normal adults. Design, Setting, and Participants This cross-sectional study was conducted using community volunteers from the Knight Alzheimer’s Disease Research Center at Washington University in St Louis. Cognitively normal participants (n = 205) underwent 7 to 14 days of actigraphy in their home environment between 2010 and 2012, in addition to clinical assessment, amyloid imaging with Pittsburgh Compound B (PiB), and cerebrospinal fluid biomarker collection. Data collected from 3 years before to 6 months after actigraphy were included. Sixteen participants were excluded owing to incomplete data collection. Main Outcomes and Measures Circadian rhythm analysis was performed on actigraphy data using 3 methods: cosinor, nonparametric, and empirical mode decomposition. Preclinical AD was assessed by longitudinal clinical assessment, amyloid imaging with PiB, and cerebrospinal fluid biomarker collection. Results Data from 189 participants were included in the analyses. The mean (SD) age was 66.6 (8.3) years, and 121 participants (64%) were women. Older age (β = .247; P = .003) and male sex (β = .170; P = .04), in the absence of amyloid pathology, were associated with a significant increase in intradaily variability, a nonparametric measure of rest-activity rhythm fragmentation, as well as decreased amplitude by several measures. After correction for age and sex, the presence of preclinical amyloid plaque pathology, assessed by positive PiB imaging (mean [SD], 0.804 [0.187] for PiB negative vs 0.875 [0.178] for PiB positive; P = .05) or increasing cerebrospinal fluid phosphorylated-tau to amyloid β 42 ratio (β = .231; P = .008), was associated with increased intradaily variability, indicating rest-activity rhythm fragmentation. Conclusions and Relevance Preclinical AD is associated with rest-activity rhythm fragmentation, independent of age or sex. Aging was also associated with circadian dysfunction independently of preclinical AD pathology, particularly in men. The presence of circadian rhythm abnormalities in the preclinical phase of AD suggests that circadian dysfunction could contribute to early disease pathogenesis or serve as a biomarker of preclinical disease.

Association of Mild Traumatic Brain Injury With and Without Loss of Consciousness With Dementia in US Military Veterans.

Abstract: Importance Traumatic brain injury (TBI) is common in both veteran and civilian populations. Prior studies have linked moderate and severe TBI with increased dementia risk, but the association between dementia and mild TBI, particularly mild TBI without loss of consciousness (LOC), remains unclear. Objective To examine the association between TBI severity, LOC, and dementia diagnosis in veterans. Design, Setting, and Participants This cohort study of all patients diagnosed with a TBI in the Veterans Health Administration health care system from October 1, 2001, to September 30, 2014, and a propensity-matched comparison group. Patients with dementia at baseline were excluded. Researchers identified TBIs through the Comprehensive TBI Evaluation database, which is restricted to Iraq and Afghanistan veterans, and the National Patient Care Database, which includes veterans of all eras. The severity of each TBI was based on the most severe injury recorded and classified as mild without LOC, mild with LOC, mild with LOC status unknown, or moderate or severe using Department of Defense or Defense and Veterans Brain Injury Center criteria. International Classification of Diseases, Ninth Revision codes were used to identify dementia diagnoses during follow-up and medical and psychiatric comorbidities in the 2 years prior to the index date. Main Outcomes and Measures Dementia diagnosis in veterans who had experienced TBI with or without LOC and control participants without TBI exposure. Results The study included 178 779 patients diagnosed with a TBI in the Veterans Health Administration health care system and 178 779 patients in a propensity-matched comparison group. Veterans had a mean (SD) age of nearly 49.5 (18.2) years at baseline; 33 250 (9.3%) were women, and 259 136 (72.5%) were non-Hispanic white individuals. Differences between veterans with and without TBI were small. A total of 4698 veterans (2.6%) without TBI developed dementia compared with 10 835 (6.1%) of those with TBI. After adjustment for demographics and medical and psychiatric comobidities, adjusted hazard ratios for dementia were 2.36 (95% CI, 2.10-2.66) for mild TBI without LOC, 2.51 (95% CI, 2.29-2.76) for mild TBI with LOC, 3.19 (95% CI, 3.05-3.33) for mild TBI with LOC status unknown, and 3.77 (95% CI, 3.63-3.91) for moderate to severe TBI. Conclusions and Relevance In this cohort study of more than 350 000 veterans, even mild TBI without LOC was associated with more than a 2-fold increase in the risk of dementia diagnosis. Studies of strategies to determine mechanisms, prevention, and treatment of TBI-related dementia in veterans are urgently needed.

Anti-Tumor Necrosis Factor Therapy and Incidence of Parkinson Disease Among Patients With Inflammatory Bowel Disease.

Abstract: Importance Despite established genetic and pathophysiologic links between inflammatory bowel disease (IBD) and Parkinson disease (PD), clinical data supporting this association remain scarce. Although systemic inflammation is considered a potential biological mechanism shared between the 2 diseases, the role of reduced systemic inflammation through IBD-directed anti–tumor necrosis factor (anti-TNF) therapy in PD risk is largely unknown. Objective To compare the incidence of PD among individuals with or without IBD and to assess whether PD risk among patients with IBD is altered by anti-TNF therapy. Design, Setting, and Participants This is a retrospective cohort study analyzing information in the Truven Health MarketScan administrative claims database and the Medicare Supplemental Database between January 1, 2000, and March 31, 2016. Individuals were selected who had at least 2 claims for IBD diagnoses, at least 6 months of follow-up, and no prior diagnosis of PD on or before the IBD index date. Exposure to Anti-TNF therapy was measured from the anti-TNF index date to the last date of anti-TNF coverage or the end of enrollment or PD index date, whichever was earliest. Incidence rates per 1000 person-years were calculated, and crude and adjusted incidence rate ratios were estimated by Poisson regression models and presented with 95% CIs. Main Outcomes and Measures Incidence of PD among patients with IBD with or without exposure to anti-TNF therapy. Results In total, 144 018 individuals with IBD were matched on age, sex, and year of index date with 720 090 unaffected controls. Of them, 1796 individuals had at least 2 PD diagnoses and at least 1 filled PD-related prescription. The mean (SD) age of individuals with IBD was 51 (17) years, and 44% were men. The incidence of PD among patients with IBD was 28% higher than that among unaffected matched controls (adjusted incidence rate ratio, 1.28; 95% CI, 1.14-1.44;P Conclusions and Relevance A higher incidence of PD was observed among patients with IBD than among individuals without IBD. Early exposure to antiinflammatory anti-TNF therapy was associated with substantially reduced PD incidence. These findings support a role of systemic inflammation in the pathogenesis of both diseases. Further studies are required to determine whether anti-TNF treatment administered to high-risk individuals may mitigate PD risk.

Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau.

Abstract: Importance The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association betweenAPOEalleles and markers of AD neuropathology in a sex-specific manner. Objective To evaluate sex differences in the association betweenAPOEand markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy. Design, Setting, and Participants This multicohort study selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals and included population-based and clinic-based samples. Inclusion in our analysis requiredAPOEgenotype data and either CSF data available for analysis. Analyses began on November 6, 2017, and were completed on December 20, 2017. Main Outcomes and Measures Biomarker analyses included levels of β-amyloid 42, total tau, and phosphorylated tau measured in CSF. Autopsy analyses included Consortium to Establish a Registry for Alzheimer’s Disease staging for neuritic plaques and Braak staging for neurofibrillary tangles. Results Of the 1798 patients in the CSF biomarker cohort, 862 were women, 226 had AD, 1690 were white, and the mean (SD) age was 70 [9] years. Of the 5109 patients in the autopsy cohort, 2813 were women, 4953 were white, and the mean (SD) age was 84 (9) years. After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction betweenAPOE-e4 and sex on CSF total tau (β = 0.41; 95% CI, 0.27-0.55;P Conclusions and Relevance We provide robust evidence of a stronger association betweenAPOE-e4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly,APOE-e4 is not differentially associated with autopsy measures of neurofibrillary tangles. Together, the sex difference in the association betweenAPOEand CSF measures of tau and the lack of a sex difference in the association with neurofibrillary tangles at autopsy suggest thatAPOEmay modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.

Definition and Consensus Diagnostic Criteria for Neurosarcoidosis: From the Neurosarcoidosis Consortium Consensus Group

Abstract: Importance The Neurosarcoidosis Consortium Consensus Group, an expert panel of physicians experienced in the management of patients with sarcoidosis and neurosarcoidosis, engaged in an iterative process to define neurosarcoidosis and develop a practical diagnostic approach to patients with suspected neurosarcoidosis. This panel aimed to develop a consensus clinical definition of neurosarcoidosis to enhance the clinical care of patients with suspected neurosarcoidosis and to encourage standardization of research initiatives that address this disease. Observations The work of this collaboration included a review of the manifestations of neurosarcoidosis and the establishment of an approach to the diagnosis of this disorder. The proposed consensus diagnostic criteria, which reflect current knowledge, provide definitions for possible, probable, and definite central and peripheral nervous system sarcoidosis. The definitions emphasize the need to evaluate patients with findings suggestive of neurosarcoidosis for alternate causal factors, including infection and malignant neoplasm. Also emphasized is the need for biopsy, whenever feasible and advisable according to clinical context and affected anatomy, of nonneural tissue to document the presence of systemic sarcoidosis and support a diagnosis of probable neurosarcoidosis or of neural tissue to support a diagnosis of definite neurosarcoidosis. Conclusions and Relevance Diverse disease presentations and lack of specificity of relevant diagnostic tests contribute to diagnostic uncertainty. This uncertainty is compounded by the absence of a pathognomonic histologic tissue examination. The diagnostic criteria we propose are designed to focus investigations on NS as accurately as possible, recognizing that multiple pathophysiologic pathways may lead to the clinical manifestations we currently term NS. Research recognizing the clinical heterogeneity of this diagnosis may open the door to identifying meaningful biologic factors that may ultimately contribute to better treatments.

Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti–α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial

Abstract: Importance Aggregated α-synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of α-synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of α-synuclein, potentially resulting in neuronal protection and slowing disease progression. Objective To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD. Design, Setting, and Participants Multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial at 8 US study centers from July 2014 to September 2016. Eligible participants were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3). Interventions Participants were enrolled into 6 ascending-dose cohorts and randomly assigned to receive PRX002 (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg) or placebo. Participants received 3 intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period. Main Outcomes and Measures Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events. Pharmacokinetic parameters included maximum PRX002 concentration, area under the curve, and half-life. Results Of the 80 participants, most were white (97.5%; n = 78) and male (80%; n = 64); median (SD) age was 58 (8.4) years. PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported. The TEAEs experienced by at least 5% of patients receiving PRX002, irrespective of relatedness to study drug, were constipation (9.1%; n = 5), infusion reaction (7.3%; n = 4), diarrhea (5.5%; n = 3), headache (5.5%; n = 3), peripheral edema (5.5%; n = 3), post–lumbar puncture syndrome (5.5%; n = 3), and upper respiratory tract infection (5.5%; n = 3). No antidrug antibodies were detected. Serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days). Rapid dose- and time-dependent mean reductions from baseline vs placebo in free serum α-synuclein levels of up to 97% were seen after a single infusion at the highest dose (F78,284= 1.66;P = .002), with similar reductions after 2 additional infusions. Mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts. Conclusions and Relevance Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral α-synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated α-synuclein in the brain. Findings support the design of an ongoing phase 2 clinical study (NCT03100149). Trial Registration ClinicalTrials.gov Identifier:NCT02157714

Chronic Meningitis Investigated via Metagenomic Next-Generation Sequencing.

Abstract: Importance Identifying infectious causes of subacute or chronic meningitis can be challenging. Enhanced, unbiased diagnostic approaches are needed. Objective To present a case series of patients with diagnostically challenging subacute or chronic meningitis using metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) supported by a statistical framework generated from mNGS of control samples from the environment and from patients who were noninfectious. Design, Setting, and Participants In this case series, mNGS data obtained from the CSF of 94 patients with noninfectious neuroinflammatory disorders and from 24 water and reagent control samples were used to develop and implement a weighted scoring metric based onzscores at the species and genus levels for both nucleotide and protein alignments to prioritize and rank the mNGS results. Total RNA was extracted for mNGS from the CSF of 7 participants with subacute or chronic meningitis who were recruited between September 2013 and March 2017 as part of a multicenter study of mNGS pathogen discovery among patients with suspected neuroinflammatory conditions. The neurologic infections identified by mNGS in these 7 participants represented a diverse array of pathogens. The patients were referred from the University of California, San Francisco Medical Center (n = 2), Zuckerberg San Francisco General Hospital and Trauma Center (n = 2), Cleveland Clinic (n = 1), University of Washington (n = 1), and Kaiser Permanente (n = 1). A weightedzscore was used to filter out environmental contaminants and facilitate efficient data triage and analysis. Main Outcomes and Measures Pathogens identified by mNGS and the ability of a statistical model to prioritize, rank, and simplify mNGS results. Results The 7 participants ranged in age from 10 to 55 years, and 3 (43%) were female. A parasitic worm (Taenia solium, in 2 participants), a virus (HIV-1), and 4 fungi (Cryptococcus neoformans,Aspergillus oryzae,Histoplasma capsulatum, andCandida dubliniensis) were identified among the 7 participants by using mNGS. Evaluating mNGS data with a weightedzscore–based scoring algorithm reduced the reported microbial taxa by a mean of 87% (range, 41%-99%) when taxa with a combined score of 0 or less were removed, effectively separating bona fide pathogen sequences from spurious environmental sequences so that, in each case, the causative pathogen was found within the top 2 scoring microbes identified using the algorithm. Conclusions and Relevance Diverse microbial pathogens were identified by mNGS in the CSF of patients with diagnostically challenging subacute or chronic meningitis, including a case of subarachnoid neurocysticercosis that defied diagnosis for 1 year, the first reported case of CNS vasculitis caused byAspergillus oryzae, and the fourth reported case ofC dubliniensismeningitis. Prioritizing metagenomic data with a scoring algorithm greatly clarified data interpretation and highlighted the problem of attributing biological significance to organisms present in control samples used for metagenomic sequencing studies.

Seizures and Encephalitis in Myelin Oligodendrocyte Glycoprotein IgG Disease vs Aquaporin 4 IgG Disease

Abstract: Importance Antibodies to myelin oligodendrocyte glycoprotein IgG (MOG-IgG) are increasingly detected in patients with non–multiple sclerosis–related demyelination, some of whom manifest a neuromyelitis optica (NMO) phenotype. Cortical involvement, encephalopathy, and seizures are rare in aquaporin 4 antibody (AQP4-IgG)–related NMO in the white European population. However, the authors encountered several patients with seizures associated with MOG-IgG disease. Objective To compare incidence of seizures and encephalitis-like presentation, or both between AQP4-IgG–positive and MOG-IgG–positive patients. Design, Setting, and Participants Retrospective case series of all patients who were seropositive for MOG-IgG (n = 34) and the last 100 patients with AQP4-IgG disease (NMO spectrum disorder) seen in the NMO service between January 2013 and December 2016, and analysis was completed January 4, 2017. All patients were seen in a tertiary neurological center, The Walton Centre NHS Foundation Trust in Liverpool, England. Main Outcomes and Measures The difference in seizure frequency between the AQP4-IgG–positive and MOG-IgG–positive patient groups was determined. Results Thirty-four patients with MOG-IgG disease (20 female) with a median age at analysis of 30.5 years (interquartile range [IQR], 15-69 years), and 100 AQP4-IgG–positive patients (86 female) with a median age at analysis of 54 years (IQR, 12-91 years) were studied. Most patients were of white race. Five of the 34 patients with MOG-IgG (14.7%) had seizures compared with 1 patient with AQP4-IgG (2-sided P Conclusions and Relevance Patients with MOG-IgG–associated disease were more likely to have seizures and encephalitis-like presentation than patients with AQP4-IgG–associated disease.

Interactive Associations of Vascular Risk and β-Amyloid Burden With Cognitive Decline in Clinically Normal Elderly Individuals: Findings From the Harvard Aging Brain Study.

Abstract: Importance Identifying asymptomatic individuals at high risk of impending cognitive decline because of Alzheimer disease is crucial for successful prevention of dementia. Vascular risk and β-amyloid (Aβ) pathology commonly co-occur in older adults and are significant causes of cognitive impairment. Objective To determine whether vascular risk and Aβ burden act additively or synergistically to promote cognitive decline in clinically normal older adults; and, secondarily, to evaluate the unique influence of vascular risk on prospective cognitive decline beyond that of commonly used imaging biomarkers, including Aβ burden, hippocampal volume, fludeoxyglucose F18–labeled (FDG) positron emission tomography (PET), and white matter hyperintensities, a marker of cerebrovascular disease. Design, Setting, and Participants In this longitudinal observational study, we examined clinically normal older adults from the Harvard Aging Brain Study. Participants were required to have baseline imaging data (FDG-PET, Aβ-PET, and magnetic resonance imaging), baseline medical data to quantify vascular risk, and at least 1 follow-up neuropsychological visit. Data collection began in 2010 and is ongoing. Data analysis was performed on data collected between 2010 and 2017. Main Outcomes and Measures Vascular risk was quantified using the Framingham Heart Study general cardiovascular disease (FHS-CVD) risk score. We measured Aβ burden with Pittsburgh Compound-B PET. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite. Models were corrected for baseline age, sex, years of education, and apolipoprotein E e4 status. Results Of the 223 participants, 130 (58.3%) were women. The mean (SD) age was 73.7 (6.0) years, and the mean (SD) follow-up time was 3.7 (1.2) years. Faster cognitive decline was associated with both a higher FHS-CVD risk score (β = −0.064; 95% CI, −0.094 to −0.033;P Conclusions and Relevance In this study, vascular risk was associated with prospective cognitive decline in clinically normal older adults, both alone and synergistically with Aβ burden. Vascular risk may complement imaging biomarkers in assessing risk of prospective cognitive decline in preclinical Alzheimer disease.

Efficacy and Safety of Deep Brain Stimulation in Tourette Syndrome: The International Tourette Syndrome Deep Brain Stimulation Public Database and Registry

Abstract: IMPORTANCE Collective evidence has strongly suggested that deep brain stimulation (DBS) is a promising therapy for Tourette syndrome.OBJECTIVE To assess the efficacy and safety of DBS in a multinat ...

Effect of pain neuroscience education combined with cognition-targeted motor control training on chronic spinal pain: a randomized clinical trial

Abstract: Importance Effective treatments for chronic spinal pain are essential to reduce the related high personal and socioeconomic costs. Objective To compare pain neuroscience education combined with cognition-targeted motor control training with current best-evidence physiotherapy for reducing pain and improving functionality, gray matter morphologic features, and pain cognitions in individuals with chronic spinal pain. Design, Setting, and Participants Multicenter randomized clinical trial conducted from January 1, 2014, to January 30, 2017, among 120 patients with chronic nonspecific spinal pain in 2 outpatient hospitals with follow-up at 3, 6, and 12 months. Interventions Participants were randomized into an experimental group (combined pain neuroscience education and cognition-targeted motor control training) and a control group (combining education on back and neck pain and general exercise therapy). Main Outcomes and Measures Primary outcomes were pain (pressure pain thresholds, numeric rating scale, and central sensitization inventory) and function (pain disability index and mental health and physical health). Results There were 22 men and 38 women in the experimental group (mean [SD] age, 39.9 [12.0] years) and 25 men and 35 women in the control group (mean [SD] age, 40.5 [12.9] years). Participants in the experimental group experienced reduced pain (small to medium effect sizes): higher pressure pain thresholds at primary test site at 3 months (estimated marginal [EM] mean, 0.971; 95% CI, –0.028 to 1.970) and reduced central sensitization inventory scores at 6 months (EM mean, –5.684; 95% CI, –10.589 to –0.780) and 12 months (EM mean, –6.053; 95% CI, –10.781 to –1.324). They also experienced improved function (small to medium effect sizes): significant and clinically relevant reduction of disability at 3 months (EM mean, –5.113; 95% CI, –9.994 to –0.232), 6 months (EM mean, –6.351; 95% CI, –11.153 to –1.550), and 12 months (EM mean, –5.779; 95% CI, –10.340 to –1.217); better mental health at 6 months (EM mean, 36.496; 95% CI, 7.998-64.995); and better physical health at 3 months (EM mean, 39.263; 95% CI, 9.644-66.882), 6 months (EM mean, 53.007; 95% CI, 23.805-82.209), and 12 months (EM mean, 32.208; 95% CI, 2.402-62.014). Conclusions and Relevance Pain neuroscience education combined with cognition-targeted motor control training appears to be more effective than current best-evidence physiotherapy for improving pain, symptoms of central sensitization, disability, mental and physical functioning, and pain cognitions in individuals with chronic spinal pain. Significant clinical improvements without detectable changes in brain gray matter morphologic features calls into question the relevance of brain gray matter alterations in this population. Trial Registration clinicaltrials.gov Identifier:NCT02098005

Comparative Effectiveness of Rituximab and Other Initial Treatment Choices for Multiple Sclerosis

Abstract: IMPORTANCE Comparative real-world effectiveness studies of initial disease-modifying treatment (DMT) choices for relapsing-remitting multiple sclerosis (RRMS) that include rituximab are lacking.OBJ ...

Association of Retinal Nerve Fiber Layer Thinning With Current and Future Cognitive Decline: A Study Using Optical Coherence Tomography.

Abstract: Importance Identifing potential screening tests for future cognitive decline is a priority for developing treatments for and the prevention of dementia. Objective To examine the potential of retinal nerve fiber layer (RNFL) thickness measurement in identifying those at greater risk of cognitive decline in a large community cohort of healthy people. Design, Setting, and Participants UK Biobank is a prospective, multicenter, community-based study of UK residents aged 40 to 69 years at enrollment who underwent baseline retinal optical coherence tomography imaging, a physical examination, and a questionnaire. The pilot study phase was conducted from March 2006 to June 2006, and the main cohort underwent examination for baseline measures from April 2007 to October 2010. Four basic cognitive tests were performed at baseline, which were then repeated in a subset of participants approximately 3 years later. We analyzed eyes with high-quality optical coherence tomography images, excluding those with eye disease or vision loss, a history of ocular or neurological disease, or diabetes. We explored associations between RNFL thickness and cognitive function using multivariable logistic regression modeling to control for demographic as well as physiologic and ocular variation. Main Outcomes and Measures Odds ratios (ORs) for cognitive performance in the lowest fifth percentile in at least 2 of 4 cognitive tests at baseline, or worsening results on at least 1 cognitive test at follow-up. These analyses were adjusted for age, sex, race/ethnicity, height, refraction, intraocular pressure, education, and socioeconomic status. Results A total of 32 038 people were included at baseline testing, for whom the mean age was 56.0 years and of whom 17 172 (53.6%) were women. A thinner RNFL was associated with worse cognitive performance on baseline assessment. A multivariable regression controlling for potential confounders showed that those in the thinnest quintile of RNFL were 11% more likely to fail at least 1 cognitive test (95% CI, 2.0%-2.1%; P = .01). Follow-up cognitive tests were performed for 1251 participants (3.9%). Participants with an RNFL thickness in the 2 thinnest quintiles were almost twice as likely to have at least 1 test score be worse at follow-up cognitive testing (quintile 1: OR, 1.92; 95% CI, 1.29-2.85; P P Conclusions and Relevance A thinner RNFL is associated with worse cognitive function in individuals without a neurodegenerative disease as well as greater likelihood of future cognitive decline. This preclinical observation has implications for future research, prevention, and treatment of dementia.

Association of excessive daytime sleepiness with longitudinal β-Amyloid accumulation in elderly persons without dementia

Abstract: Importance Aging is associated with excessive daytime sleepiness (EDS), which has been linked to cognitive decline in the elderly. However, whether EDS is associated with the pathologic processes of Alzheimer disease remains unclear. Objective To investigate whether EDS at baseline is associated with a longitudinal increase in regional β-amyloid (Aβ) accumulation in a cohort of elderly individuals without dementia. Design, Setting, and Participants This prospective analysis included participants enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study in Olmsted County, Minnesota. Of 2900 participants, 2172 (74.9%) agreed to undergo carbon 11–labeled Pittsburgh compound B positron emission tomography (PiB-PET). We included 283 participants 70 years or older without dementia who completed surveys assessing sleepiness at baseline and had at least 2 consecutive PiB-PET scans from January 1, 2009, through July 31, 2016, after excluding 45 (13.7%) who had a comorbid neurologic disorder. Main Outcomes and Measures Excessive daytime sleepiness was defined as an Epworth Sleepiness Scale score of at least 10. The difference in Aβ levels between the 2 consecutive scans (ΔPiB) in Aβ-susceptible regions (prefrontal, anterior cingulate, posterior cingulate-precuneus, and parietal) was determined. Multiple linear regression models were fit to explore associations between baseline EDS and ΔPiB while adjusting for baseline age, sex, presence of the apolipoprotein E e4 allele, educational level, baseline PiB uptake, global PiB positivity (standardized uptake value ratio ≥1.4), physical activity, cardiovascular comorbidities (obesity, hypertension, hyperlipidemia, and diabetes), reduced sleep duration, respiratory symptoms during sleep, depression, and interval between scans. Results Of the initial 283 participants, mean (SD) age was 77.1 (4.8) years; 204 (72.1%) were men and 79 (27.9%) were women. Sixty-three participants (22.3%) had EDS. Baseline EDS was significantly associated with increased regional Aβ accumulation in the anterior cingulate (B coefficient = 0.031; 95% CI, 0.001-0.061; P = .04), posterior cingulate-precuneus (B coefficient = 0.038; 95% CI, 0.006-0.069; P = .02), and parietal (B coefficient = 0.033; 95% CI, 0.001-0.065; P = .04) regions. Association of EDS with longitudinal Aβ accumulation was stronger in participants with baseline global PiB positivity in the anterior cingulate (B coefficient = 0.065; 95% CI, 0.010-0.118; P = .02) and cingulate-precuneus (B coefficient = 0.068; 95% CI, 0.009-0.126; P = .02) regions. Conclusions and Relevance Baseline EDS was associated with increased longitudinal Aβ accumulation in elderly persons without dementia, suggesting that those with EDS may be more vulnerable to pathologic changes associated with Alzheimer disease. Further work is needed to elucidate whether EDS is a clinical marker of greater sleep instability, synaptic or network overload, or neurodegeneration of wakefulness-promoting centers. Early identification of patients with EDS and treatment of underlying sleep disorders could reduce Aβ accumulation in this vulnerable group.

Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease

Abstract: Importance It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as early as possible. Individuals with autosomal dominant forms of AD can provide clues as to which and when biological changes are reliably present prior to the onset of clinical symptoms. Objective To characterize the associations between amyloid and tau deposits in the brains of cognitively unimpaired and impaired carriers of presenilin 1 (PSEN1) E280A mutation. Design, Setting, and Participants In this cross-sectional imaging study, we leveraged data from a homogeneous autosomal dominant AD kindred, which allowed us to examine measurable tau deposition as a function of individuals’ proximity to the expected onset of dementia. Cross-sectional measures of carbon 11–labeled Pittsburgh Compound B positron emission tomography (PET) and flortaucipir F 18 (previously known as AV 1451, T807) PET imaging were assessed in 24PSEN1E280A kindred members (age range, 28-55 years), including 12 carriers, 9 of whom were cognitively unimpaired and 3 of whom had mild cognitive impairment, and 12 cognitively unimpaired noncarriers. Main Outcomes and Measures We compared carbon 11–labeled Pittsburgh Compound B PET cerebral with cerebellar distribution volume ratios as well as flortaucipir F 18 PET cerebral with cerebellar standardized uptake value ratios in mutation carriers and noncarriers. Spearman correlations characterized the associations between age and mean cortical Pittsburgh Compound B distribution volume ratio levels or regional flortaucipir standardized uptake value ratio levels in both groups. Results Of the 24 individuals, the mean (SD) age was 38.0 (7.4) years, or approximately 6 years younger than the expected onset of clinical symptoms in carriers. Compared with noncarriers, cognitively unimpaired mutation carriers had elevated mean cortical Pittsburgh Compound B distribution volume ratio levels in their late 20s, and 7 of 9 carriers older than 30 years reached the threshold for amyloidosis (distribution volume ratio level > 1.2). Elevated levels of tau deposition were seen within medial temporal lobe regions in amyloid-positive mutation carriers 6 years before clinical onset of AD in this kindred. Substantial tau deposition in the neocortex was only observed in 1 unimpaired carrier and in those with mild cognitive impairment. β-Amyloid uptake levels were diffusely elevated in unimpaired carriers approximately 15 years prior to expected onset of mild cognitive impairment. In carriers, higher levels of tau deposition were associated with worse performance on the Mini-Mental State Examination (entorhinal cortex:r = −0.60;P = .04; inferior temporal lobe:r = −0.54;P = .06) and the Consortium to Establish a Registry for Alzheimer Disease Word List Delayed Recall (entorhinal cortex:r = −0.86;P Conclusions and Relevance The present findings add to the growing evidence that molecular markers can characterize biological changes associated with AD in individuals who are still cognitively unimpaired. The findings also suggest that tau PET imaging may be useful as a biomarker to distinguish individuals at high risk to develop the clinical symptoms of AD and to track disease progression.

Association of Retinal Neurodegeneration on Optical Coherence Tomography With Dementia: A Population-Based Study

Abstract: Importance Retinal structures may serve as a biomarker for dementia, but longitudinal studies examining this link are lacking. Objective To investigate the association of inner retinal layer thickness with prevalent and incident dementia in a general population of Dutch adults. Design, Setting, and Participants From September 2007 to June 2012, participants from the prospective population-based Rotterdam Study who were 45 years and older and had gradable retinal optical coherence tomography images and at baseline were free from stroke, Parkinson disease, multiple sclerosis, glaucoma, macular degeneration, retinopathy, myopia, hyperopia, and optic disc pathology were included. They were followed up until January 1, 2015, for the onset of dementia. Exposures Inner retinal layer thicknesses (ie, retinal nerve fiber layer [RNFL]) and ganglion cell–inner plexiform layer (GC-IPL) thicknesses measured on optical coherence tomography images. Main Outcomes and Measures Odds ratios and hazard ratios for incident dementia per SD decrease in retinal layer thickness adjusted for age, sex, education, and cardiovascular risk factors. Results Of 5065 individuals eligible for optical coherence tomography scanning, 3289 (64.9%) (mean [SD] age 68.9 [9.9] years, 1879 [57%] women) were included in the analysis. Of these 3289 individuals, 41 (1.2%) already had dementia. Thinner GC-IPL was associated with prevalent dementia (odds ratio per SD decrease in GC-IPL, 1.37 [95% CI, 0.99-1.90]). No association was found of RNFL with prevalent dementia. During 14 674 person-years of follow-up (mean [SD], 4.5 [1.6] years), 86 individuals (2.6%) developed dementia of whom 68 (2.1%) had Alzheimer disease. Thinner RNFL at baseline was associated with an increased risk of developing dementia (hazard ratio per SD decrease in RNFL, 1.44 [95% CI, 1.19-1.75]), which was similar for Alzheimer disease (hazard ratio, 1.43 [95% CI, 1.15-1.78]). No association was found between GC-IPL thickness and incident dementia (hazard ratio, 1.13 [95% CI, 0.90-1.43]). Conclusions and Relevance Thinner RNFL is associated with an increased risk of dementia, including Alzheimer disease, suggesting that retinal neurodegeneration may serve as a preclinical biomarker for dementia.

Advances in Understanding the Pathophysiology of Lacunar Stroke: A Review.

Abstract: Importance Stroke is the second leading cause of death in the world, and nearly one-third of ischemic strokes are lacunar strokes (LSs) or small subcortical infarcts Although smaller in size, they create large problems, leaving many patients with intellectual and physical disabilities Because there are limitations in understanding the underlying pathophysiology of LS, the development of novel therapies has been slow Observations When the termlacunewas described in the 1800s, its underlying pathophysiological basis was obscure In the 1960s, C Miller Fisher, MD, performed autopsy studies that showed that vessels supplying lacunes displayed segmental arteriolar disorganization, characterized by vessel enlargement, hemorrhage, and fibrinoid deposition For these pathologic changes, he coined the termlipohyalinosis Since that time, few attempts have been made to reconcile this pathologic description with modern mechanisms of cerebral small vessel disease (CSVD) During the past 6 years, progress has been made in understanding the clinical mechanisms, imaging characteristics, and genetic basis of LS Conclusions and Relevance Questions persist regarding the order of events related to the initiation and progression of CSVD, how LS is related to other sequelae of CSVD, and whether LS is part of a systemic disease process The relative roles of aging, oxidative stress, mechanical stress, genetic predisposition, and other vascular risk factors should be further studied, especially in the era of widespread antihypertensive use Although understanding of endothelial dysfunction has increased, future work on the role of media and adventitial dysfunction should be explored Recent advances in mapping the brain vasculome may generate new hypotheses The investigation of new therapeutic targets, aimed at reversing CSVD processes and promoting neural repair after LS, depends upon further understanding these basic mechanisms

Placebo Effects on the Neurologic Pain Signature: A Meta-analysis of Individual Participant Functional Magnetic Resonance Imaging Data.

Abstract: Importance Placebo effects reduce pain and contribute to clinical analgesia, but after decades of research, it remains unclear whether placebo treatments mainly affect nociceptive processes or other processes associated with pain evaluation. Objective We conducted a systematic, participant-level meta-analysis to test the effect of placebo treatments on pain-associated functional neuroimaging responses in the neurologic pain signature (NPS), a multivariate brain pattern tracking nociceptive pain. Data Sources Medline (PubMed) was searched from inception to May 2015; the search was augmented with results from previous meta-analyses and expert recommendations. Study Selection Eligible studies were original investigations that were published in English in peer-reviewed journals and that involved functional neuroimaging of the human brain with evoked pain delivered under stimulus intensity-matched placebo and control conditions. The authors of all eligible studies were contacted and asked to provide single-participant data. Data Extraction and Synthesis Data were collected between December 2015 and November 2017 following the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data guidelines. Results were summarized across participants and studies in a random-effects model. Main Outcomes and Measures The main, a priori outcome was NPS response; pain reports were assessed as a secondary outcome. Results We obtained data from 20 of 28 identified eligible studies, resulting in a total sample size of 603 healthy individuals. The NPS responses to painful stimulation compared with baseline conditions were positive in 575 participants (95.4%), with a very large effect size (g = 2.30 [95% CI, 1.92 to 2.69]), confirming its sensitivity to nociceptive pain in this sample. Placebo treatments showed significant behavioral outcomes on pain ratings in 17 of 20 studies (85%) and in the combined sample (g = −0.66 [95% CI, −0.80 to −0.53]). However, placebo effects on the NPS response were significant in only 3 of 20 studies (15%) and were very small in the combined sample (g = −0.08 [95% CI, −0.15 to −0.01]). Similarly, analyses restricted to studies with low risk of bias (g = −0.07 [95% CI, −0.15 to 0.00]) indicated very small effects, and analyses of just placebo responders (g = −0.22 [95% CI, −0.34 to −0.11]) indicated small effects, as well. Conclusions and Relevance Placebo treatments have moderate analgesic effects on pain reports. The very small effects on NPS, a validated measure that tracks levels of nociceptive pain, indicate that placebo treatments affect pain via brain mechanisms largely independent of effects on bottom-up nociceptive processing.

Adeno-Associated Viral Vector (Serotype 2)-Nerve Growth Factor for Patients With Alzheimer Disease: A Randomized Clinical Trial.

Abstract: Importance Nerve growth factor (NGF) is an endogenous neurotrophic factor that prevents the death and augments the functional state of cholinergic neurons of the basal forebrain, a cell population that undergoes extensive degeneration in Alzheimer disease (AD). Objective To determine whether stereotactically guided intracerebral injections of adeno-associated viral vector (serotype 2)–nerve growth factor (AAV2-NGF) are well tolerated and exhibit preliminary evidence of impact on cognitive decline in mild to moderate AD-associated dementia. Design, Setting, and Participants In a multicenter phase 2 trial, 49 participants with mild to moderate AD were randomly assigned in a 1:1 ratio to receive stereotactically guided intracerebral injections of AAV2-NGF or sham surgery. Participants were enrolled between November 2009 and December 2012. Analyses began in February 2015. The study was conducted at 10 US academic medical centers. Eligibility required a diagnosis of mild to moderate dementia due to AD and individuals aged 55 to 80 years. A total of 39 participants did not pass screening; the most common reason was Mini-Mental State Examination scores below cutoff. Analyses were intention-to-treat. Interventions Stereotactically guided intracerebral injections of AAV2-NGF into the nucleus basalis of Meynert of each hemisphere or sham surgery. Main Outcomes and Measures Change from baseline on the Alzheimer’s Disease Assessment Scale–cognitive subscale at month 24. Results Among 49 participants, 21 (43%) were women, 42 (86%) self-identified as white, and the mean (SD) age was 68 (6.4) years. AAV2-NGF was safe and well-tolerated through 24 months. No significant difference was noted between the treatment group and placebo on the primary outcome measure, the Alzheimer’s Disease Assessment Scale–cognitive subscale (mean [SD] score, 14.52 [4.66] vs 9.11 [4.65], P = .17). Conclusions and Relevance This multicenter randomized clinical trial demonstrated the feasibility of sham-surgery–controlled stereotactic gene delivery studies in patients with AD. AAV2-NGF delivery was well-tolerated but did not affect clinical outcomes or selected AD biomarkers. Pathological confirmation of accurate gene targeting is needed. Trial Registration clinicaltrials.gov IdentifierNCT00876863

Transcranial Direct Current Stimulation vs Sham Stimulation to Treat Aphasia After Stroke: A Randomized Clinical Trial.

Abstract: Importance Aphasia is a debilitating language disorder for which behavioral speech therapy is the most efficient treatment, but therapy outcomes are variable and full recovery is not always achieved. It remains unclear if adjunctive brain stimulation (anodal transcranial direct current stimulation [A-tDCS]) applied during aphasia therapy can improve outcomes. Objective To examine the futility of studying A-tDCS as an adjunctive intervention during speech therapy to improve speech production (naming) for individuals with long-term poststroke aphasia. Design, Setting, and Participants Double-blinded, prospective randomized clinical trial using a futility design to test adjunctive A-tDCS during speech therapy. The setting was an outpatient clinic. Enrollment of individuals began in August 2012 and was completed in March 2017, and the duration of follow-up was 6 months. Analyses began in April 2017. The study recruited from a volunteer sample, and 89 patients were screened. Patients with long-term (>6 months) aphasia due to 1 previous left hemisphere stroke were enrolled. In comparing A-tDCS and sham tDCS, patients were matched based on site (University of South Carolina or Medical University of South Carolina), baseline age, type of aphasia, and aphasia severity. Interventions Outpatient speech therapy for 3 weeks (15 sessions, 45 minutes each) combined with either A-tDCS vs sham tDCS applied to preserved left temporal lobe regions. Main Outcomes and Measures The primary outcome was the ability to name common objects, assessed twice before and after therapy. Results A total of 74 patients were enrolled. Participants had a mean (SD) age of 60 (10) years, had 15 (2) years of education, and were 44 (40) months from stroke onset. There were 52 men (70%) and 62 non-Hispanic white individuals (84%). Most were retired or not employed (59 [80%]). Broca aphasia was the most common aphasia type (39 [52.7%]). The adjusted mean (SE) change from pretreatment baseline in correct naming was 13.9 (2.4) words (95% CI, 9.0-18.7) for A-tDCS and 8.2 (2.2) words (95% CI, 3.8-12.6) for sham tDCS, with mean (SE) A-tDCS difference of 5.7 (3.3) words (95% CI, −0.9 to 12.3), indicating a relative 70% increase in correct naming for A-tDCS relative to sham. The futility hypothesisPvalue was .90, indicating failure to reject the null hypothesis and, therefore, providing no evidence that further study of A-tDCS is futile. No serious adverse events were associated with A-tDCS. Conclusions and Relevance Our findings provide motivation to proceed with another trial to study the effect of A-tDCS on the outcome of aphasia treatment in individuals poststroke. Anodal tDCS during speech therapy is feasible and potentially transformative for aphasia treatment and should be further studied. Trial Registration ClinicalTrials.gov Identifier:NCT01686373

Safety and Efficacy of Atorvastatin for Chronic Subdural Hematoma in Chinese Patients: A Randomized ClinicalTrial

Abstract: Importance Chronic subdural hematoma (CSDH) is a trauma-associated condition commonly found in elderly patients. Surgery is currently the treatment of choice, but it carries a significant risk of recurrence and death. Nonsurgical treatments remain limited and ineffective. Our recent studies suggest that atorvastatin reduces hematomas and improves the clinical outcomes of patients with CSDH. Objective To investigate the safety and therapeutic efficacy of atorvastatin to nonsurgically treat patients with CSDH. Design, Setting, and Participants The Effect of Atorvastatin on Chronic Subdural Hematoma (ATOCH) randomized, placebo-controlled, double-blind phase II clinical trial was conducted in multiple centers in China from February 2014 to November 2015. For this trial, we approached 254 patients with CSDH who received a diagnosis via a computed tomography scan; of these, 200 (78.7%) were enrolled because 23 patients (9.1%) refused to participate and 31 (12.2%) were disqualified. Interventions Patients were randomly assigned to receive either 20 mg of atorvastatin or placebo daily for 8 weeks and were followed up for an additional 16 weeks. Main Outcomes and Measures The primary outcome was change in hematoma volume (HV) by computed tomography after 8 weeks of treatment. The secondary outcomes included HV measured at the 4th, 12th, and 24th weeks and neurological function that was evaluated using the Markwalder grading scale/Glasgow Coma Scale and the Barthel Index at the 8th week. Results One hundred ninety-six patients received treatment (169 men [86.2%]; median [SD] age, 63.6 [14.2] years). The baseline HV and clinical presentations were similar between patients who were taking atorvastatin (98 [50%]) and the placebo (98 [50%]). After 8 weeks, the HV reduction in patients who were taking atorvastatin was 12.55 mL more than those taking the placebo (95% CI, 0.9-23.9 mL; P = .003). Forty-five patients (45.9%) who were taking atorvastatin significantly improved their neurological function, but only 28 (28.6%) who were taking the placebo did, resulting in an adjusted odds ratio of 1.957 for clinical improvements (95% CI, 1.07-3.58; P = .03). Eleven patients (11.2%) who were taking atorvastatin and 23 (23.5%) who were taking the placebo underwent surgery during the trial for an enlarging hematoma and/or a deteriorating clinical condition (hazard ratio, 0.47; 95% CI, 0.24-0.92; P = .03). No significant adverse events were reported. Conclusions and Relevance Atorvastatin may be a safe and efficacious nonsurgical alternative for treating patients with CSDH. Trial Registration ClinicalTrials.gov Identifier:NCT02024373