Publications by authors named "Karen Marder"

228 Publications

Genome-wide association studies of LRRK2 modifiers of Parkinson's disease.

Ann Neurol 2021 May 2. Epub 2021 May 2.

23andMe, Inc., Sunnyvale, California, U.S.A.

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.

Methods: We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genome-wide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.

Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; P-value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genome-wide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these two proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: P-value = 1.1E-07; age-at-onset top variant: P-value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.

Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. This article is protected by copyright. All rights reserved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.26094DOI Listing
May 2021

Impact of IMPACT: Longitudinal Analysis of an Integrated Participant Scheduling System in a Clinical Research Setting.

AMIA Annu Symp Proc 2020 25;2020:283-292. Epub 2021 Jan 25.

Columbia University, New York, NY i0032, USA.

Rapidly increasing costs have been a major threat to our clinical research enterprise. Improvement in appointment scheduling is a crucial means to boost efficiency and save cost in clinical research and has been well studied in the outpatient setting. This study reviews nearly 5 years of usage data of an integrated scheduling system implemented at Columbia University/New York Presbyterian (CUIMC/NYP) called IMPACT and provides original insights into the challenges faced by a clinical research facility. Briefly, the IMPACT data shows that high rates of room and resource changes correlate with rescheduled appointments and that rescheduled visits are more likely to be attended than non-rescheduled visits. We highlight the differing roles of schedulers, coordinators, and investigators, and propose a highly accurate predictive model of participant no-shows in a research setting. This study sheds light on ways to reduce overall cost and improve the care we offer to clinical research participants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075470PMC
January 2021

Association of Dual LRRK2 G2019S and GBA Variations With Parkinson Disease Progression.

JAMA Netw Open 2021 Apr 1;4(4):e215845. Epub 2021 Apr 1.

Department of Neurology, Mount Sinai Beth Israel, and Icahn School of Medicine, Mount Sinai, New York, New York.

Importance: Despite a hypothesis that harboring a leucine-rich repeat kinase 2(LRRK2) G2019S variation and a glucocerebrosidase (GBA) variant would have a combined deleterious association with disease pathogenesis, milder clinical phenotypes have been reported in dual LRRK2 and GBA variations Parkinson disease (PD) than in GBA variation PD alone.

Objective: To evaluate the association of LRRK2 G2019S and GBA variants with longitudinal cognitive and motor decline in PD.

Design, Setting, And Participants: This longitudinal cohort study of continuous measures in LRRK2 PD, GBA PD, LRRK2/GBA PD, and wild-type idiopathic PD used pooled annual visit data ranging from 2004 to 2019 from the Mount Sinai Beth Israel, Parkinson Disease Biomarker Program, Harvard Biomarkers Study, Ashkenazi Jewish-LRRK2-Consortium, Parkinson Progression Marker Initiative, and SPOT-PD studies. Patients who were screened for GBA and LRRK2 variations and completed either a motor or cognitive assessment were included. Data were analyzed from May to July 2020.

Main Outcomes And Measures: The associations of LRRK2 G2019S and GBA genotypes on the rate of decline in Montreal Cognitive Assessment (MoCA) and Movement Disorders Society-Unified Parkinson Disease Rating Scale-Part III scores were examined using linear mixed effects models with PD duration as the time scale.

Results: Among 1193 individuals with PD (mean [SD] age, 66.6 [9.9] years; 490 [41.2%] women), 128 (10.7%) had GBA PD, 155 (13.0%) had LRRK2 PD, 21 (1.8%) had LRRK2/GBA PD, and 889 (74.5%) had idiopathic PD. Patients with GBA PD had faster decline in MoCA than those with LRRK2/GBA PD (B [SE], -0.31 [0.09] points/y; P < .001), LRRK2 PD (B [SE], -0.33 [0.09] points/y; P < .001), or idiopathic PD (B [SE], -0.23 [0.08] points/y; P = .005). There was a LRRK2 G2019S × GBA interaction in MoCA decline (B [SE], 0.22 [0.11] points/y; P = .04), but not after excluding severe GBA variations (B [SE], 0.12 [0.11] points/y; P = .28). Patients with GBA PD had significantly worse motor progression compared with those with idiopathic PD (B [SE], 0.49 [0.22] points/y; P = .03) or LRRK2 PD (B [SE], 0.77 [0.26] points/y; P = .004).

Conclusions And Relevance: These findings suggest that longitudinal cognitive decline in patients with GBA PD was more severe than in those with LRRK2/GBA PD, which more closely resembled LRRK2 PD. This further supports the notion of a dominant association of LRRK2 on GBA in individuals who carry both and raises the possibility of an LRRK2 × GBA interaction. However, the biological basis of a dominant association or interaction is not clear and is apparently contrary to basic investigations. Study of a larger cohort of individuals with severe GBA variation is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2021.5845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060834PMC
April 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

The TCR repertoire of α-synuclein-specific T cells in Parkinson's disease is surprisingly diverse.

Sci Rep 2021 Jan 11;11(1):302. Epub 2021 Jan 11.

Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA.

The self-antigen α-synuclein (α-syn) was recently shown to be associated with Parkinson's disease (PD). Here we mapped the T cell receptor (TCR) repertoire of α-syn-specific T cells from six PD patients. The self-antigen α-syn-specific repertoire was compared to the repertoire of T cells specific for pertussis (PT), as a representative foreign antigen that most individuals are exposed to, revealing that the repertoire for α-syn was as diverse as the repertoire for PT. The diversity of PT-specific clonotypes was similar between individuals with PD diagnosis and age-matched healthy controls. We found that the TCR repertoire was specific to each PD patient, and no shared TCRs among patients were defined, likely due to differences in HLA expression that select for different subsets of epitope-specific TCR rearrangements. This study provides the first characterization of α-syn-specific TCR clonotypes in individuals with PD. Antigen-specific TCRs can serve as immunotherapeutics and diagnostics, and means to track longitudinal changes in specific T cells, and disease progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-79726-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801678PMC
January 2021

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington's Disease Patients-A Randomized Phase 2 Clinical Trial.

J Clin Med 2020 Nov 16;9(11). Epub 2020 Nov 16.

Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington's disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington's Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9113682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696926PMC
November 2020

Challenges and opportunities for improving the landscape for Lewy body dementia clinical trials.

Alzheimers Res Ther 2020 10 29;12(1):137. Epub 2020 Oct 29.

Lewy Body Dementia Association, S.W., Lilburn, GA, USA.

Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson's disease dementia, affects over a million people in the USA and has a substantial impact on patients, caregivers, and society. Symptomatic treatments for LBD, which can include cognitive, neuropsychiatric, autonomic, sleep, and motor features, are limited with only two drugs (cholinesterase inhibitors) currently approved by regulatory agencies for dementia in LBD. Clinical trials represent a top research priority, but there are many challenges in the development and implementation of trials in LBD. To address these issues and advance the field of clinical trials in the LBDs, the Lewy Body Dementia Association formed an Industry Advisory Council (LBDA IAC), in addition to its Research Center of Excellence program. The LBDA IAC comprises a diverse and collaborative group of experts from academic medical centers, pharmaceutical industries, and the patient advocacy foundation. The inaugural LBDA IAC meeting, held in June 2019, aimed to bring together this group, along with representatives from regulatory agencies, to address the topic of optimizing the landscape of LBD clinical trials. This review highlights the formation of the LBDA IAC, current state of LBD clinical trials, and challenges and opportunities in the field regarding trial design, study populations, diagnostic criteria, and biomarker utilization. Current gaps include a lack of standardized clinical assessment tools and evidence-based management strategies for LBD as well as difficulty and controversy in diagnosing LBD. Challenges in LBD clinical trials include the heterogeneity of LBD pathology and symptomatology, limited understanding of the trajectory of LBD cognitive and core features, absence of LBD-specific outcome measures, and lack of established standardized biologic, imaging, or genetic biomarkers that may inform study design. Demands of study participation (e.g., travel, duration, and frequency of study visits) may also pose challenges and impact trial enrollment, retention, and outcomes. There are opportunities to improve the landscape of LBD clinical trials by harmonizing clinical assessments and biomarkers across cohorts and research studies, developing and validating outcome measures in LBD, engaging the patient community to assess research needs and priorities, and incorporating biomarker and genotype profiling in study design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13195-020-00703-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597002PMC
October 2020

Predictive testing for neurodegenerative diseases in the age of next-generation sequencing.

J Genet Couns 2020 Oct 8. Epub 2020 Oct 8.

Dept. of Neurology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.

The availability and cost of next-generation sequencing (NSG) now allow testing large numbers of genes simultaneously. However, the gold standard for predictive testing has been to test only for a known family mutation or confirmed family disease. The goal of this study was to investigate the psychological impact of predictive testing for autosomal dominant neurodegenerative diseases without a known family mutation using next-generation sequencing panels compared to single-gene testing of a known family mutation. Fourteen individuals from families with a known mutation and 10 individuals with unknown family mutations participated. Participants completed questionnaires on demographics, genetic knowledge, and psychological measures of anxiety, depression, perceived personal control, rumination, and intolerance to uncertainty at baseline and 1 and 6 months after receiving results. Decision regret was measured 1 and 6 months after receiving results. Participants completed a modified Huntington disease genetic testing protocol with genetic counseling and neurological and psychological evaluation. Genetic testing of either the known family mutation or an NGS panel of neurodegenerative disease genes was performed. Semi-structured interviews were performed at 6 months post-results about their experience. Two-sample t tests were performed on data collected at each time point to identify significant between-group differences in demographic variables, baseline psychological scores, and baseline genetic knowledge scores. Within-group change over time was assessed by a mixed-effects model. Results of this study indicate that NGS panels for predictive testing for neurodegenerative disease are safe and beneficial to participants when performed within a modified HD protocol. Though significant differences in psychological outcomes were found, these differences may have been driven by genetic results and baseline psychological differences between individuals within the groups. Participants did not regret their decision to test and were largely pleased with the testing protocol.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgc4.1342DOI Listing
October 2020

T Cell Responses to Neural Autoantigens Are Similar in Alzheimer's Disease Patients and Age-Matched Healthy Controls.

Front Neurosci 2020 27;14:874. Epub 2020 Aug 27.

Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, United States.

Alzheimer's disease (AD), a chronic multifactorial and complex neurodegenerative disorder is a leading cause of dementia. Recently, neuroinflammation has been hypothesized as a contributing factor to AD pathogenesis. The role of adaptive immune responses against neuronal antigens, which can either confer protection or induce damage in AD, has not been fully characterized. Here, we measured T cell responses to several potential antigens of neural origin including amyloid precursor protein (APP), amyloid beta (Aβ), tau, α-synuclein, and transactive response DNA binding protein (TDP-43) in patients with AD and age-matched healthy controls (HC). Antigen-specific T cell reactivity was detected for all tested antigens, and response to tau-derived epitopes was particularly strong, but no significant differences between individuals with AD and age-matched HC were identified. We also did not observe any correlation between the antigen-specific T cell responses and clinical variables including age, gender, years since diagnosis and cognitive score. Additionally, further characterization did not reveal any differences in the relative frequency of major Peripheral Blood Mononuclear Cells (PBMC) subsets, or in the expression of genes between AD patients and HC. These observations have not identified a key role of neuronal antigen-specific T cell responses in AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2020.00874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481378PMC
August 2020

Time-varying Hazards Model for Incorporating Irregularly Measured, High-Dimensional Biomarkers.

Stat Sin 2020 Jul;30(3):1605-1632

Columbia University.

Clinical studies with time-to-event outcomes often collect measurements of a large number of time-varying covariates over time (e.g., clinical assessments or neuroimaging biomarkers) to build time-sensitive prognostic model. An emerging challenge is that due to resource-intensive or invasive (e.g., lumbar puncture) data collection process, biomarkers may be measured infrequently and thus not available at every observed event time point. Lever-aging all available, infrequently measured time-varying biomarkers to improve prognostic model of event occurrence is an important and challenging problem. In this paper, we propose a kernel-smoothing based approach to borrow information across subjects to remedy infrequent and unbalanced biomarker measurements under a time-varying hazards model. A penalized pseudo-likelihood function is proposed for estimation, and an efficient augmented penalization minimization algorithm related to the alternating direction method of multipliers (ADMM) is adopted for computation. Under some regularity conditions to carefully control approximation bias and stochastic variability, we show that even in the presence of ultra-high dimensionality, the proposed method selects important biomarkers with high probability. Through extensive simulation studies, we demonstrate superior performance in terms of estimation and selection performance compared to alternative methods. Finally, we apply the proposed method to analyze a recently completed real world study to model time to disease conversion using longitudinal, whole brain structural magnetic resonance imaging (MRI) biomarkers, and show a substantial improvement in performance over current standards including using baseline measures only.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5705/ss.202017.0375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497773PMC
July 2020

Authors' replies to the comments of Koga et al. on "Movement disorders rounds: A case of missing pathology in a patient with LRRK2 Parkinson's disease".

Parkinsonism Relat Disord 2020 Sep 5. Epub 2020 Sep 5.

Department of Neurology, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, 710 West 168th Street, New York, NY, 10032, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2020.08.037DOI Listing
September 2020

Quantifying Postural Control in Premanifest and Manifest Huntington Disease Using Wearable Sensors.

Neurorehabil Neural Repair 2020 09 16;34(9):771-783. Epub 2020 Jul 16.

G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.

. Impairments in postural control in Huntington disease (HD) have important consequences for daily functioning. This observational study systematically examined baseline postural control and the effect of sensory attenuation and sensory enhancement on postural control across the spectrum of HD. . Participants (n = 39) included healthy controls and individuals in premanifest (pHD) and manifest stages (mHD) of HD. Using wearable sensors, postural control was assessed according to (1) postural set (sit vs stand), (2) sensory attenuation using clinical test of sensory integration, and (3) sensory enhancement with gaze fixation. Outcomes included sway smoothness, amplitude, and frequency. . Based on postural set, pHD reduced postural sway in sitting relative to standing, whereas mHD had pronounced sway in standing and sitting, highlighting a baseline postural deficit. During sensory attenuation, postural control in pHD deteriorated relative to controls when proprioceptive demands were high (eyes closed on foam), whereas mHD had significant deterioration of postural control when proprioception was attenuated (eyes open and closed on foam). Finally, gaze fixation improved sway smoothness, amplitude, and frequency in pHD; however, no benefit was observed in mHD. . Systematic examination of postural control revealed a fundamental postural deficit in mHD, which further deteriorates when proprioception is challenged. Meanwhile, postural deficits in pHD are detectable when proprioceptive challenge is high. Sensory enhancing strategies using gaze fixation to benefit posture may be useful when introduced well before motor diagnosis. These findings encourage further examination of wearable sensors as part of routine clinical assessments in HD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1545968320939560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501191PMC
September 2020

Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs.

Genome Biol 2020 06 29;21(1):153. Epub 2020 Jun 29.

Hackensack-Meridian Health Center for Discovery and Innovation, Nutley, NJ, 07110, USA.

Background: Mapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). The advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified.

Results: We perform whole genome methyl-seq on diverse normal cells and tissues and three cancer types. After excluding imprinting, the data pinpoint 15,112 high-confidence ASM differentially methylated regions, of which 1838 contain SNPs in strong linkage disequilibrium or coinciding with GWAS peaks. ASM frequencies are increased in cancers versus matched normal tissues, due to widespread allele-specific hypomethylation and focal allele-specific hypermethylation in poised chromatin. Cancer cells show increased allele switching at ASM loci, but disruptive SNPs in specific classes of CTCF and transcription factor binding motifs are similarly correlated with ASM in cancer and non-cancer. Rare somatic mutations affecting these same motif classes track with de novo ASM. Allele-specific transcription factor binding from ChIP-seq is enriched among ASM loci, but most ASM differentially methylated regions lack such annotations, and some are found in otherwise uninformative "chromatin deserts."

Conclusions: ASM is increased in cancers but occurs by a shared mechanism involving disruptive SNPs in CTCF and transcription factor binding sites in both normal and neoplastic cells. Dense ASM mapping in normal plus cancer samples reveals candidate rSNPs that are difficult to find by other approaches. Together with GWAS data, these rSNPs can nominate specific transcriptional pathways in susceptibility to autoimmune, cardiometabolic, neuropsychiatric, and neoplastic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-020-02059-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322865PMC
June 2020

α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson's disease.

Nat Commun 2020 04 20;11(1):1875. Epub 2020 Apr 20.

Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA.

A diagnosis of motor Parkinson's disease (PD) is preceded by a prolonged premotor phase with accumulating neuronal damage. Here we examined the temporal relation between α-synuclein (α-syn) T cell reactivity and PD. A longitudinal case study revealed that elevated α-syn-specific T cell responses were detected prior to the diagnosis of motor PD, and declined after. The relationship between T cell reactivity and early PD in two independent cohorts showed that α-syn-specific T cell responses were highest shortly after diagnosis of motor PD and then decreased. Additional analysis revealed significant association of α-syn-specific T cell responses with age and lower levodopa equivalent dose. These results confirm the presence of α-syn-reactive T cells in PD and show that they are most abundant immediately after diagnosis of motor PD. These cells may be present years before the diagnosis of motor PD, suggesting avenues of investigation into PD pathogenesis and potential early diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-15626-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171193PMC
April 2020

Research criteria for the diagnosis of prodromal dementia with Lewy bodies.

Neurology 2020 04 2;94(17):743-755. Epub 2020 Apr 2.

From the Newcastle University (I.G.M., A.J.T., P.D., J.P.T.); Mayo Clinic (T.J.F.), Jacksonville; University of Strasbourg (F.B.); Mayo Clinic (B.F.B., K.K.), Rochester; Nagoya University (H.F.), Kawasaki Memorial Hospital; Istituto Neurologico "Carlo Besta" (C.M., P.T.), Milan; Cambridge University (F.M.S.); McGill University (R.B.P.); King's College London and Stavanger University Hospital (D.A.); University of Exeter (C.B.); University of Chieti-Pescara (L.B.); Istanbul Faculty of Medicine (M.E.); University of Miami Miller School of Medicine (J.E.G.); University of California (D.G., D.P.S.), San Diego; Feinberg School of Medicine (J.G.G.); Massachusetts General Hospital (S.N.G.); Columbia University Irving Medical Center (L.S.H., K.S.M.); Osaka University (M.I.); Lou Ruvo Center of Brain Health (J.B.L.), Cleveland Clinic; University of Sydney (S.J.G.L.); Sunnybrook Health Sciences Centre (M.M.), University of Toronto; VA Puget Sound & University of Washington (D.W.T.); University College London (Z.W.).

The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000009323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274845PMC
April 2020

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

JAMA Neurol 2020 06;77(6):755-763

Columbia University Irving Medical Center, New York, New York.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.

Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings.

Conclusions And Relevance: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2020.0367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483960PMC
June 2020

Estimating disease onset from change points of markers measured with error.

Biostatistics 2020 Jan 30. Epub 2020 Jan 30.

Department of Statistics, Texas A&M University, College Station, TX 77843, USA.

Huntington disease is an autosomal dominant, neurodegenerative disease without clearly identified biomarkers for when motor-onset occurs. Current standards to determine motor-onset rely on a clinician's subjective judgment that a patient's extrapyramidal signs are unequivocally associated with Huntington disease. This subjectivity can lead to error which could be overcome using an objective, data-driven metric that determines motor-onset. Recent studies of motor-sign decline-the longitudinal degeneration of motor-ability in patients-have revealed that motor-onset is closely related to an inflection point in its longitudinal trajectory. We propose a nonlinear location-shift marker model that captures this motor-sign decline and assesses how its inflection point is linked to other markers of Huntington disease progression. We propose two estimating procedures to estimate this model and its inflection point: one is a parametric method using nonlinear mixed effects model and the other one is a multi-stage nonparametric approach, which we developed. In an empirical study, the parametric approach was sensitive to correct specification of the mean structure of the longitudinal data. In contrast, our multi-stage nonparametric procedure consistently produced unbiased estimates regardless of the true mean structure. Applying our multi-stage nonparametric estimator to Neurobiological Predictors of Huntington Disease, a large observational study of Huntington disease, leads to earlier prediction of motor-onset compared to the clinician's subjective judgment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/biostatistics/kxz068DOI Listing
January 2020

Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies.

Acta Neuropathol Commun 2020 01 29;8(1). Epub 2020 Jan 29.

Neurology Service, University of Coimbra Hospital, Coimbra, Portugal.

Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-020-0879-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990558PMC
January 2020

Movement disorders rounds: A case of missing pathology in a patient with LRRK2 Parkinson's disease.

Parkinsonism Relat Disord 2020 05 9;74:76-77. Epub 2019 Nov 9.

Department of Neurology, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, 710 West 168th Street, New York, NY, 10032, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2019.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374981PMC
May 2020

Genetic testing for Parkinson disease: current practice, knowledge, and attitudes among US and Canadian movement disorders specialists.

Genet Med 2020 03 4;22(3):574-580. Epub 2019 Nov 4.

Struthers Parkinson's Center, Golden Valley, MN, USA.

Purpose: Genetic testing for Parkinson disease (PD) has not been widely used in clinical practice. In preparation for upcoming precision medicine-designed clinical trials for GBA and LRRK2, we evaluated movement disorders specialists' current practice, knowledge, attitudes, and barriers to genetic testing in PD.

Methods: An anonymous questionnaire was sent to movement disorders specialists at 146 Parkinson Study Group (PSG) sites in the United States (n = 131) and Canada (n = 15) to assess their knowledge and attitudes about genetic testing for PD.

Results: One hundred seventy-eight (47.6%) PSG clinicians completed the questionnaire. Forty-one percent of respondents had not referred any PD patients for genetic testing in the last year and >80% reported referring fewer than 11 patients over the same period. Most common reasons for not referring for genetic testing included lack of insurance coverage/cost to the patient and lack of perceived utility. On a scale of 0-100, the mean level of comfort in respondents' own ability to genetically counsel PD patients on GBA and LRRK2 was 52 (SD = 28). Sixty percent of clinicians correctly answered all questions about the inheritance and penetrance of GBA and LRRK2 variants.

Conclusions: There is an urgent need to increase knowledge and reduce practical barriers to genetic counseling and testing in PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0684-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056638PMC
March 2020

Genetic testing for Parkinson disease: current practice, knowledge, and attitudes among US and Canadian movement disorders specialists.

Genet Med 2020 03 4;22(3):574-580. Epub 2019 Nov 4.

Struthers Parkinson's Center, Golden Valley, MN, USA.

Purpose: Genetic testing for Parkinson disease (PD) has not been widely used in clinical practice. In preparation for upcoming precision medicine-designed clinical trials for GBA and LRRK2, we evaluated movement disorders specialists' current practice, knowledge, attitudes, and barriers to genetic testing in PD.

Methods: An anonymous questionnaire was sent to movement disorders specialists at 146 Parkinson Study Group (PSG) sites in the United States (n = 131) and Canada (n = 15) to assess their knowledge and attitudes about genetic testing for PD.

Results: One hundred seventy-eight (47.6%) PSG clinicians completed the questionnaire. Forty-one percent of respondents had not referred any PD patients for genetic testing in the last year and >80% reported referring fewer than 11 patients over the same period. Most common reasons for not referring for genetic testing included lack of insurance coverage/cost to the patient and lack of perceived utility. On a scale of 0-100, the mean level of comfort in respondents' own ability to genetically counsel PD patients on GBA and LRRK2 was 52 (SD = 28). Sixty percent of clinicians correctly answered all questions about the inheritance and penetrance of GBA and LRRK2 variants.

Conclusions: There is an urgent need to increase knowledge and reduce practical barriers to genetic counseling and testing in PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0684-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056638PMC
March 2020

Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls.

Mov Disord 2019 09 26;34(9):1392-1398. Epub 2019 Jul 26.

Department of Neurology, Mount Sinai Beth Israel Medical Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls.

Methods: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients.

Results: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients.

Conclusions: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.27807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754269PMC
September 2019

Hierarchical Data-Driven Analysis of Clinical Symptoms Among Patients With Parkinson's Disease.

Front Neurol 2019 21;10:531. Epub 2019 May 21.

Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Mutations in the LRRK2 and GBA genes are the most common inherited causes of Parkinson's disease (PD). Studies exploring phenotypic differences based on genetic status used hypothesis-driven data-gathering and statistical-analyses focusing on specific symptoms, which may influence the validity of the results. We aimed to explore phenotypic expression in idiopathic PD (iPD) patients, G2019S-LRRK2-PD, and GBA-PD using a data-driven approach, allowing screening of large numbers of features while controlling selection bias. Data was collected from 1525 Ashkenazi Jews diagnosed with PD from the Tel-Aviv Medical center; 161 G2019S-LRRK2-PD, 222 GBA-PD, and 1142 iPD (no G2019S-LRRK2 or any of the 7 AJ GBA mutations tested). Data included 771 measures: demographics, cognitive, physical and neurological functions, performance-based measures, and non-motor symptoms. The association of the genotypes with each of the measures was tested while accounting for age at motor symptoms onset, gender, and disease duration; -values were reported and corrected in a hierarchical approach for an average over the selected measures false discovery rate control, resulting in 32 measures. GBA-PD presented with more severe symptoms expression while LRRK2-PD had more benign symptoms compared to iPD. GBA-PD presented greater cognitive and autonomic involvement, more frequent hyposmia and REM sleep behavior symptoms while these were less frequent among LRRK2-PD compared to iPD. Using a data-driven analytical approach strengthens earlier studies and extends them to portray a possible unique disease phenotype based on genotype among AJ PD. Such findings could help direct a more personalized therapeutic approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2019.00531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536639PMC
May 2019

Patient Knowledge and Attitudes towards Genetic Testing in Parkinson's Disease Subjects with Deep Brain Stimulation.

Parkinsons Dis 2019 21;2019:3494609. Epub 2019 Apr 21.

Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.

Objectives: As genetic testing is becoming more widely commercially available for Parkinson's disease (PD) and may have implications regarding clinical outcomes for deep brain stimulation (DBS) and other therapies, we aimed to determine patient knowledge and attitudes towards genetic testing.

Methods: A sample of 88 PD subjects with bilateral STN-DBS completed a Genetic Attitudes Questionnaire (GAQ). Knowledge and attitudes towards genetic testing were assessed.

Results: The mean percent of correct responses regarding genetic testing knowledge was 58.5%. Nearly 90% of subjects were unfamiliar with Genetic Information Nondiscrimination Act (GINA). The most important reasons subjects cited in deciding whether to undergo genetic testing included (1) to be a candidate for clinical trials if positive, (2) to learn that they do not carry a mutation, and (3) because a healthcare provider had recommended it. Individuals who influence decision-making include spouses and children. About 88% of subjects would share results with spouses, children, and siblings.

Discussion: These results reveal that there is a major knowledge gap regarding genetic testing in PD and the implications of testing results on treatment, work, insurance, and privacy. Also, subjects would mainly seek genetic testing to participate in clinical trials, with spouses and children being the key stakeholders in decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/3494609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501170PMC
April 2019

The choice not to undergo genetic testing for Huntington disease: Results from the PHAROS study.

Clin Genet 2019 07 15;96(1):28-34. Epub 2019 May 15.

Department of Neurology, University of Rochester, Rochester, NY.

Rates of genetic testing in Huntington disease (HD) are lower than was predicted before direct DNA testing became available. Clinicians often do not have in-depth conversations with people at risk who chose not to test. We queried 733 research subjects who chose not to learn their HD gene status when enrolling in the Prospective Huntington At-Risk Observational Study, carried out between 1999 and 2008. Lack of an effective cure or treatment (66% of subjects) and inability to undo knowledge (66%) were the major reasons cited for choosing not to undergo HD DNA testing. Most subjects were not concerned about the length or burden of the testing process (61% and 59%, respectively). Subjects were optimistic that a treatment to improve symptoms or postpone onset would be developed within the next 10 years (56% and 53%, respectively), but they had less certainty about the prospects to prevent HD onset (36%). This is the first large, systematic study of why people at risk for HD choose not to undergo genetic testing. Attitudes about how people at risk for HD approach this life-altering choice should be reassessed as new treatments develop, and as clinical trials now require genetic testing at entry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13529DOI Listing
July 2019

Correction: Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study.

Genet Med 2019 Oct;21(10):2407

Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA.

The original version of this Article contained an error in the undergraduate degree awarded to the author Ian Halim, which was incorrectly given as BS. This has now been corrected to BA in both the PDF and HTML versions of the Article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0528-8DOI Listing
October 2019

Heritability and genetic variance of dementia with Lewy bodies.

Neurobiol Dis 2019 07 3;127:492-501. Epub 2019 Apr 3.

Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Sweden.

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2019.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588425PMC
July 2019

Evaluation of the cost and effectiveness of diverse recruitment methods for a genetic screening study.

Genet Med 2019 10 1;21(10):2371-2380. Epub 2019 Apr 1.

Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA.

Purpose: Recruitment of participants from diverse backgrounds is crucial to the generalizability of genetic research, but has proven challenging. We retrospectively evaluated recruitment methods used for a study on return of genetic results.

Methods: The costs of study design, development, and participant enrollment were calculated, and the characteristics of the participants enrolled through the seven recruitment methods were examined.

Results: A total of 1118 participants provided consent, a blood sample, and questionnaire data. The estimated cost across recruitment methods ranged from $579 to $1666 per participant and required a large recruitment team. Recruitment methods using flyers and staff networks were the most cost-efficient and resulted in the highest completion rate. Targeted sampling that emphasized the importance of Latino/a participation, utilization of translated materials, and in-person recruitments contributed to enrolling a demographically diverse sample.

Conclusions: Although all methods were deployed in the same hospital or neighborhood and shared the same staff, each recruitment method was different in terms of cost and characteristics of the enrolled participants, suggesting the importance of carefully choosing the recruitment methods based on the desired composition of the final study sample. This analysis provides information about the effectiveness and cost of different methods to recruit adults for genetic research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0497-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213972PMC
October 2019