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1.
Mov Disord ; 37(3): 513-524, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34859493

RESUMEN

BACKGROUND: Mevidalen is a selective positive allosteric modulator (PAM) of the dopamine D1 receptor subtype. OBJECTIVE: To assess the safety and efficacy of mevidalen for treatment of cognition in patients with Lewy body dementia (LBD). METHODS: PRESENCE was a phase 2, 12-week study in participants with LBD (N = 344) randomly assigned (1:1:1:1) to daily doses of mevidalen (10, 30, or 75 mg) or placebo. The primary outcome measure was change from baseline on Cognitive Drug Research Continuity of Attention (CoA) composite score. Secondary outcomes included Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-cog13 ), Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). Numerous safety measures were collected. RESULTS: Mevidalen failed to meet primary or secondary cognition endpoints. Mevidalen resulted in significant, dose-dependent improvements of MDS-UPDRS total score (sum of Parts I-III, 10 mg P < 0.05, 30 mg P < 0.05, 75 mg P < 0.01, compared to placebo). The 30 mg and 75 mg mevidalen doses significantly improved ADCS-CGIC scores compared to placebo (minimal or better improvement: 30 mg P < 0.01, 75 mg P < 0.01; moderate or better improvement: 30 mg P < 0.05, 75 mg P < 0.001). Increases in blood pressure, adverse events, and cardiovascular serious adverse events were most pronounced at the 75 mg dose. CONCLUSIONS: Mevidalen harnesses a novel mechanism of action that improves motor symptoms associated with LBD on top of standard of care while improving or not worsening non-motor symptoms associated with traditional dopaminergic therapy. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Enfermedad de Alzheimer , Enfermedad por Cuerpos de Lewy , Fármacos Neuroprotectores , Cognición , Método Doble Ciego , Humanos , Enfermedad por Cuerpos de Lewy/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico
2.
Alzheimers Dement ; 16(8): 1134-1145, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32573913

RESUMEN

INTRODUCTION: Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD. METHODS: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes. RESULTS: Suggestive associations (P < 1.0 × 10-6 ) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10-7 ), chromosome 7 (rs60465337,P = 4.06 × 10-7 ) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10-7 ), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10-7 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10-7 ) and 4 (rs1304013, P = 7.73 × 10-7 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified. DISCUSSION: Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact.


Asunto(s)
Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Disfunción Cognitiva/etiología , Disfunción Cognitiva/genética , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino
3.
Headache ; 58(10): 1689-1696, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30426478

RESUMEN

BACKGROUND: Migraine impacts more than 36 million people in the United States and 1 billion people worldwide. Despite the increasing availability of acute and preventive therapies, there is still tremendous unmet need. Potential treatments in development include monoclonal antibodies (mAbs). Appropriate use of these "biologic" treatments will necessitate an understanding of the aspects that distinguish them from traditional medications. AIM: Many drug classes are prescribed for migraine treatment, but all have limitations. Recently, calcitonin gene-related peptide (CGRP) activity has shown a significant promise as a target for preventive therapy. In this review, we provide an overview of the potential role of CGRP mAbs in migraine, with a focus on their design, pharmacokinetics, safety, and immunogenicity. CONCLUSIONS: The CGRP mAbs are an innovative new therapy for migraine and address the need for effective and tolerable preventive options. MAbs, including those that target CGRP or its receptor, bind to a target with high specificity and affinity and lead to few off-target adverse effects, although mechanism-based adverse reactions may occur. Unlike other therapeutic antibodies used to treat neurologic disease, CGRP mAbs do not have a target within the immune system and have been designed to avoid altering the immune system. The safety and efficacy of mAbs against CGRP or its receptors are being investigated in clinical development programs, and the first of these therapies has received regulatory approval in the United States.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Trastornos Migrañosos/prevención & control , Anticuerpos Antiidiotipos/biosíntesis , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Péptido Relacionado con Gen de Calcitonina/inmunología , Péptido Relacionado con Gen de Calcitonina/fisiología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/efectos adversos , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/fisiopatología , Receptores de Péptido Relacionado con el Gen de Calcitonina/inmunología , Receptores de Péptido Relacionado con el Gen de Calcitonina/fisiología
4.
BMC Genet ; 17: 16, 2016 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-26738766

RESUMEN

BACKGROUND: The serotonin 2A receptor is widely implicated in genetic association studies and remains an important drug target for psychiatric, neurological, and cardiovascular conditions. RNA sequencing redefined the architecture of the serotonin 2A receptor gene (HTR2A), revealing novel mRNA transcript isoforms utilizing unannotated untranslated regions of the gene. Expression of these untranslated regions is modulated by common single nucleotide polymorphisms (SNPs), namely rs6311. Previous studies did not fully capture the complexity of the sense- and antisense-encoded transcripts with respect to novel exons in the HTR2A gene locus. Here, we comprehensively catalogued exons and RNA isoforms for both HTR2A and HTR2A-AS1 using RNA-Seq from human prefrontal cortex and multiple mouse tissues. We subsequently tested associations between expression of newfound gene features and common SNPs in humans. RESULTS: We find that the human HTR2A gene spans ~66 kilobases and consists of 7, rather than 4 exons. Furthermore, the revised human HTR2A-AS1 gene spans ~474 kilobases and consists of 18, rather than 3 exons. Three HTR2A exons directly overlap with HTR2A-AS1 exons, suggesting potential for complementary nucleotide interactions. The repertoire of possible mouse Htr2a splice isoforms is remarkably similar to humans and we also find evidence for overlapping sense-antisense transcripts in the same relative positions as the human transcripts. rs6311 and SNPs in high linkage disequilibrium are associated with HTR2A-AS1 expression, in addition to previously described associations with expression of the extended 5' untranslated region of HTR2A. CONCLUSIONS: Our proposed HTR2A and HTR2A-AS1 gene structures dramatically differ from current annotations, now including overlapping exons on the sense and anti-sense strands. We also find orthologous transcript isoforms expressed in mice, providing opportunities to elucidate the biological roles of the human isoforms using a model system. Associations between rs6311 and expression of HTR2A and HTR2A-AS1 suggest this polymorphism is capable of modulating the expression of the sense or antisense transcripts. Still unclear is whether these SNPs act directly on the expression of the sense or antisense transcripts and whether overlapping exons are capable of interacting through complimentary base-pairing. Additional studies are necessary to determine the extent and nature of interactions between the SNPs and the transcripts prior to interpreting these findings in the context of phenotypes associated with HTR2A.


Asunto(s)
ADN sin Sentido , Exones , Receptor de Serotonina 5-HT2A/genética , Empalme Alternativo , Animales , Humanos , Ratones , Polimorfismo de Nucleótido Simple , Corteza Prefrontal/metabolismo , Sitios de Empalme de ARN , Esquizofrenia/genética , Alineación de Secuencia , Transcripción Genética
5.
Alzheimers Dement ; 11(7): 792-814, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26194313

RESUMEN

INTRODUCTION: Genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) have been crucial in advancing the understanding of Alzheimer's disease (AD) pathophysiology. Here, we provide an update on sample collection, scientific progress and opportunities, conceptual issues, and future plans. METHODS: Lymphoblastoid cell lines and DNA and RNA samples from blood have been collected and banked, and data and biosamples have been widely disseminated. To date, APOE genotyping, genome-wide association study (GWAS), and whole exome and whole genome sequencing data have been obtained and disseminated. RESULTS: ADNI genetic data have been downloaded thousands of times, and >300 publications have resulted, including reports of large-scale GWAS by consortia to which ADNI contributed. Many of the first applications of quantitative endophenotype association studies used ADNI data, including some of the earliest GWAS and pathway-based studies of biospecimen and imaging biomarkers, as well as memory and other clinical/cognitive variables. Other contributions include some of the first whole exome and whole genome sequencing data sets and reports in healthy controls, mild cognitive impairment, and AD. DISCUSSION: Numerous genetic susceptibility and protective markers for AD and disease biomarkers have been identified and replicated using ADNI data and have heavily implicated immune, mitochondrial, cell cycle/fate, and other biological processes. Early sequencing studies suggest that rare and structural variants are likely to account for significant additional phenotypic variation. Longitudinal analyses of transcriptomic, proteomic, metabolomic, and epigenomic changes will also further elucidate dynamic processes underlying preclinical and prodromal stages of disease. Integration of this unique collection of multiomics data within a systems biology framework will help to separate truly informative markers of early disease mechanisms and potential novel therapeutic targets from the vast background of less relevant biological processes. Fortunately, a broad swath of the scientific community has accepted this grand challenge.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Biomarcadores/metabolismo , Disfunción Cognitiva/genética , Apolipoproteínas E/genética , Bases de Datos Bibliográficas/estadística & datos numéricos , Progresión de la Enfermedad , Estudios de Asociación Genética , Humanos , Proteínas de Transporte de Membrana/genética , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Neuroimagen
6.
Mol Pain ; 10: 37, 2014 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-24934217

RESUMEN

BACKGROUND: Genetic causes of exaggerated or reduced pain sensitivity in humans are well known. Recently, single nucleotide polymorphisms (SNPs) in the gene P2RX7, coding for the ATP-gated ion channel P2X7, have been described that cause gain-of-function (GOF) and loss-of-function (LOF), respectively of this channel. Importantly, P2RX7 SNPs have been associated with more or less severe pain scores in patient suffering of post-mastectomy pain and osteoarthritis. RESULTS: The functional consequences of some P2RX7 SNPs (rs208294 (His155Tyr), rs1718119 (Ala348Thr) and rs3751143 (Glu496Ala)) were studied in recombinant cells in vitro. Our findings suggest a correlation between GOF and LOF of P2X7 and actual channel protein expression. Both channel and pore function for these mutant P2X7 receptors changed in parallel to protein levels. On the other hand, the mutant receptors did not differ in their sensitivity to known P2X7 agonists and antagonists. We further demonstrated that in patients with diabetic peripheral neuropathic pain (DPNP), the presence of the GOF SNPs rs208294 (His155Tyr) and rs1718119 (Ala348Thr) is associated, in females, with higher pain intensity scores. CONCLUSIONS: Our present results confirm the physiological relevance of some of the SNPs in the P2RX7 gene and show that the presence of these genetic variants correlates with pain sensitivity also in a diabetic neuropathic pain patient population.


Asunto(s)
Neuropatías Diabéticas/genética , Regulación de la Expresión Génica/genética , Polimorfismo de Nucleótido Simple/genética , Receptores Purinérgicos P2X7/genética , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/farmacología , Análisis de Varianza , Benzoxazoles/metabolismo , Calcio/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Genotipo , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Inhibidores de Agregación Plaquetaria/farmacología , Antagonistas del Receptor Purinérgico P2X/farmacología , Compuestos de Quinolinio/metabolismo , Transfección
7.
Neuroepidemiology ; 43(3-4): 194-205, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25402421

RESUMEN

BACKGROUND: We sought to identify optimal approaches by calibrating longitudinal cognitive performance across studies with different neuropsychological batteries. METHODS: We examined four approaches to calibrate cognitive performance in nine longitudinal studies of Alzheimer's disease (AD) (n = 10,875): (1) common test, (2) standardize and average available tests, (3) confirmatory factor analysis (CFA) with continuous indicators, and (4) CFA with categorical indicators. To compare precision, we determined the minimum sample sizes needed to detect 25% cognitive decline with 80% power. To compare criterion validity, we correlated cognitive change from each approach with 6-year changes in average cortical thickness and hippocampal volume using available MRI data from the AD Neuroimaging Initiative. RESULTS: CFA with categorical indicators required the smallest sample size to detect 25% cognitive decline with 80% power (n = 232) compared to common test (n = 277), standardize-and-average (n = 291), and CFA with continuous indicators (n = 315) approaches. Associations with changes in biomarkers changes were the strongest for CFA with categorical indicators. CONCLUSIONS: CFA with categorical indicators demonstrated greater power to detect change and superior criterion validity compared to other approaches. It has wide applicability to directly compare cognitive performance across studies, making it a good way to obtain operational phenotypes for genetic analyses of cognitive decline among people with AD.


Asunto(s)
Enfermedad de Alzheimer/psicología , Cognición , Estudios Longitudinales , Pruebas Neuropsicológicas/normas , Anciano , Anciano de 80 o más Años , Análisis Factorial , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados
8.
Neurology ; 102(5): e208061, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38386949

RESUMEN

BACKGROUND AND OBJECTIVES: Zagotenemab (LY3303560), a monoclonal antibody that preferentially targets misfolded, extracellular, aggregated tau, was assessed in the PERISCOPE-ALZ phase 2 study to determine its ability to slow cognitive and functional decline relative to placebo in early symptomatic Alzheimer disease (AD). METHODS: Participants were enrolled across 56 sites in North America and Japan. Key eligibility criteria included age of 60-85 years, Mini-Mental State Examination score of 20-28, and intermediate levels of brain tau on PET imaging. In this double-blind study, participants were equally randomized to 1,400 mg or 5,600 mg of zagotenemab, or placebo (IV infusion every 4 weeks for 100 weeks). The primary outcome was change on the Integrated AD Rating Scale (iADRS) assessed by a Bayesian Disease Progression model. Secondary measures include mixed model repeated measures analysis of additional cognitive and functional endpoints as well as biomarkers of AD pathology. RESULTS: A total of 360 participants (mean age = 75.4 years; female = 52.8%) were randomized, and 218 completed the treatment period. Demographics and baseline characteristics were reasonably balanced among arms. The mean disease progression ratio (proportional decline in the treated vs placebo group) with 95% credible intervals for the iADRS was 1.10 (0.959-1.265) for the zagotenemab low-dose group and 1.05 (0.907-1.209) for the high-dose, where a ratio less than 1 favors the treatment group. Secondary clinical endpoint measures failed to show a drug-placebo difference in favor of zagotenemab. No treatment effect was demonstrated by flortaucipir PET, volumetric MRI, or neurofilament light chain (NfL) analyses. A dose-related increase in plasma phosphorylated tau181 and total tau was demonstrated. Zagotenemab treatment groups reported a higher incidence of adverse events (AEs) (85.1%) compared with the placebo group (74.6%). This difference was not attributable to any specific AE or category of AEs. DISCUSSION: In participants with early symptomatic AD, zagotenemab failed to achieve significant slowing of clinical disease progression compared with placebo. Imaging biomarker and plasma NfL findings did not show evidence of pharmacodynamic activity or disease modification. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT03518073. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with early symptomatic AD, zagotenemab does not slow clinical disease progression.


Asunto(s)
Enfermedad de Alzheimer , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/psicología , Anticuerpos Monoclonales/uso terapéutico , Teorema de Bayes , Progresión de la Enfermedad , Método Doble Ciego , Resultado del Tratamiento , Masculino
9.
Digit Biomark ; 7(1): 54-62, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37404864

RESUMEN

Introduction: PRESENCE was a phase 2 clinical trial assessing the efficacy of mevidalen, a D1 receptor positive allosteric modulator, for symptomatic treatment of Lewy body dementia (LBD). Mevidalen demonstrated improvements in motor and non-motor features of LBD, global functioning, and actigraphy-measured activity and daytime sleep. Adverse events (AEs) of fall were numerically increased in mevidalen-treated participants. Methods: A subset of PRESENCE participants wore a wrist actigraphy device for 2-week periods pre-, during, and posttreatment. Actigraphy sleep and activity measures were derived per period and analyzed to assess for their association with participants' reports of an AE of fall. Prespecified baseline and treatment-emergent clinical characteristics were also included in the retrospective analysis of falls. Independent-samples t test and χ2 test were performed to compare the means and proportions between individuals with/without falls. Results: A trend toward more falls was observed with mevidalen treatment (31/258 mevidalen-treated vs. 4/86 in placebo-treated participants: p = 0.12). Higher body mass index (BMI) (p < 0.05), more severe disease measured by baseline Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II (p < 0.05), and a trend toward improved Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13) (p = 0.06) were associated with individuals with falls. No statistically significant associations with falls and treatment-emergent changes were observed. Conclusion: The association of falls with worse baseline disease severity and higher BMI and overall trend toward improvements on cognitive and motor scales suggest that falls in PRESENCE may be related to increased activity in mevidalen-treated participants at greater risk for falling. Future studies to confirm this hypothesis using fall diaries and digital assessments are necessary.

10.
Parkinsonism Relat Disord ; 109: 105355, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36905719

RESUMEN

INTRODUCTION: Few late-stage clinical trials in Parkinson's disease (PD) have produced evidence on the clinical validity of sensor-based digital measurements of daily life activities to detect responses to treatment. The objective of this study was to assess whether digital measures from patients with mild-to-moderate Lewy Body Dementia demonstrate treatment effects during a randomized Phase 2 trial. METHODS: Substudy within a 12-week trial of mevidalen (placebo vs 10, 30, or 75 mg), where 70/344 patients (comparable to the overall population) wore a wrist-worn multi-sensor device. RESULTS: Treatment effects were statistically significant by conventional clinical assessments (Movement Disorder Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS] sum of Parts I-III and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change [ADCS-CGIC] scores) in the full study cohort at Week 12, but not in the substudy. However, digital measurements detected significant effects in the substudy cohort at week 6, persisting to week 12. CONCLUSIONS: Digital measurements detected treatment effects in a smaller cohort over a shorter period than conventional clinical assessments. TRIAL REGISTRATION: clinicaltrials.gov, NCT03305809.


Asunto(s)
Enfermedad de Alzheimer , Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Humanos , Enfermedad por Cuerpos de Lewy/tratamiento farmacológico , Muñeca , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/diagnóstico
11.
J Parkinsons Dis ; 12(6): 1991-2004, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35694933

RESUMEN

BACKGROUND: PRESENCE was a Phase 2 trial assessing mevidalen for symptomatic treatment of Lewy body dementia (LBD). Participants received daily doses (10, 30, or 75 mg) of mevidalen (LY3154207) or placebo for 12 weeks. OBJECTIVE: To evaluate if frequent cognitive and motor tests using an iPad app and wrist-worn actigraphy to track activity and sleep could detect mevidalen treatment effects in LBD. METHODS: Of 340 participants enrolled in PRESENCE, 238 wore actigraphy for three 2-week periods: pre-, during, and post-intervention. A subset of participants (n = 160) enrolled in a sub-study using an iPad trial app with 3 tests: digital symbol substitution (DSST), spatial working memory (SWM), and finger-tapping. Compliance was defined as daily test completion or watch-wearing ≥23 h/day. Change from baseline to week 12 (app) or week 8 (actigraphy) was used to assess treatment effects using Mixed Model Repeated Measures analysis. Pearson correlations between sensor-derived features and clinical endpoints were assessed. RESULTS: Actigraphy and trial app compliance was > 90% and > 60%, respectively. At baseline, daytime sleep positively correlated with Epworth Sleepiness Scale score (p < 0.01). Physical activity correlated with improvement on Movement Disorder Society -Unified Parkinson Disease Rating Scale (MDS-UPDRS) part II (p < 0.001). Better scores of DSST and SWM correlated with lower Alzheimer Disease Assessment Scale -Cognitive 13-Item Scale (ADAS-Cog13) (p < 0.001). Mevidalen treatment (30 mg) improved SWM (p < 0.01), while dose-dependent decreases in daytime sleep (10 mg: p < 0.01, 30 mg: p < 0.05, 75 mg: p < 0.001), and an increase in walking minutes (75 mg dose: p < 0.001) were observed, returning to baseline post-intervention. CONCLUSION: Devices used in the LBD population achieved adequate compliance and digital metrics detected statistically significant treatment effects.


Asunto(s)
Enfermedad por Cuerpos de Lewy , Fármacos Neuroprotectores , Enfermedad de Parkinson , Enfermedad de Alzheimer , Biomarcadores , Cognición , Humanos , Enfermedad por Cuerpos de Lewy/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología
12.
J Parkinsons Dis ; 11(3): 1381-1392, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33720850

RESUMEN

BACKGROUND: Characterizing patients with Parkinson's disease (PD) and cognitive impairment is important toward understanding their natural history. OBJECTIVE: Understand clinical, treatment, and cost characteristics of patients with PD pre- and post-cognitive impairment (memory loss/mild cognitive impairment/dementia or dementia treatment) recognition. METHODS: 2,711 patients with PD newly diagnosed with cognitive impairment (index) were identified using administrative claims data. They were matched (1:1) on age and gender to patients with PD and no cognitive impairment (controls). These two cohorts were compared on patient characteristics, healthcare resource utilization, and total median costs for 3 years pre- and post-index using Chi-square tests, t-tests, and Wilcoxon rank-sum tests. Logistic regression was used to identify factors predicting cognitive impairment. RESULTS: Comorbidity indices for patients with cognitive impairment increased during the 6-year study period, especially after the index. Enrollment in Medicare Advantage Prescription Drug plans vs. commercial (OR = 1.60), dual Medicare/Medicaid eligibility (OR = 1.36), cerebrovascular disease (OR = 1.24), and PD medication use (OR = 1.46) were associated with a new cognitive impairment diagnosis (all p < 0.05). A greater proportion of patients with cognitive impairment had hospitalizations and emergency department visits and higher median total healthcare costs than controls for each year pre- and post-index. CONCLUSION: In patients with PD newly diagnosed with cognitive impairment, comorbidity burden, hospitalizations, emergency department visits, and total costs peaked 1-year pre- and post-identification. These data coupled with recommendations for annual screening for cognitive impairment in PD support the early diagnosis and management of cognitive impairment in order to optimize care for patients and their caregivers.


Asunto(s)
Disfunción Cognitiva , Enfermedad de Parkinson , Anciano , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/terapia , Costos de la Atención en Salud , Humanos , Medicare , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/terapia , Estados Unidos/epidemiología
13.
Alzheimers Res Ther ; 13(1): 124, 2021 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-34238345

RESUMEN

In 2019, the Lewy Body Dementia Association formed an Industry Advisory Council to bring together a collaborative group of stakeholders with the goal of accelerating clinical research into Lewy body dementia treatments. At the second annual meeting of the Industry Advisory Council, held virtually on June 18, 2020, the key members presented ongoing and planned efforts toward the council's goals. The meeting also featured a discussion about the effects of the COVID-19 pandemic on Lewy body dementia clinical research, lessons learned from that experience, and how those lessons can be applied to the design and conduct of future clinical trials. This report provides a brief summary of the meeting proceedings with a focus on efforts to improve and adapt future Lewy body dementia clinical research.


Asunto(s)
COVID-19 , Enfermedad por Cuerpos de Lewy , Humanos , Enfermedad por Cuerpos de Lewy/epidemiología , Pandemias , SARS-CoV-2
14.
Alzheimers Res Ther ; 12(1): 137, 2020 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-33121510

RESUMEN

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.


Asunto(s)
Enfermedad de Alzheimer , Enfermedad por Cuerpos de Lewy , Inhibidores de la Colinesterasa , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico , Enfermedad por Cuerpos de Lewy/tratamiento farmacológico
15.
J Am Geriatr Soc ; 66(5): 969-975, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29608782

RESUMEN

OBJECTIVES: To examine the effect of the Medicare Annual Wellness Visit (AWV) on the detection of cognitive impairment and on follow-up cognitive care for older adults. DESIGN: Retrospective matched-cohort study. SETTING: United States. PARTICIPANTS: A 5% random sample of fee-for-service Medicare beneficiaries continuously enrolled for 12 months before and after an index ambulatory visit occurring from 2011 to 2013 with no claims evidence of cognitive impairment before index. MEASUREMENTS: Outcomes include 12-month post-index visit claims-based measurements of cognitive impairment, including new Alzheimer's disease and related dementia (ADRD) diagnoses; medications for ADRD; and cognitive care-related diagnostic examination such as neurobehavioral testing, brain imaging, and blood tests for thyroid-stimulating hormone (TSH), serum B12, folate, and syphilis. We also measured changes in burden of anticholinergic medication. RESULTS: There were no clinically relevant differences between the AWV and control groups in the rates of incident ADRD diagnoses (6.16% vs 6.86%, p<.001) and initiation of ADRD medications (1.00% vs 1.08%, p=.15), although there were differences favoring the AWV group in rates of TSH (39.80% vs 28.36%, p<.001), B12 (9.41% vs 6.97%, p<.001), folate (4.76% vs 3.72%, p<.001), and neurobehavioral (0.75% vs 0.55%, p<.001) testing. CONCLUSIONS: Although the AWV is correlated with an increase in some measures of cognitive care, such as laboratory testing for reversible causes of cognitive impairment, it does not appear to substantially increase recognition of undetected ADRD.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Disfunción Cognitiva/diagnóstico , Medicare , Atención Primaria de Salud/métodos , Anciano , Anciano de 80 o más Años , Planes de Aranceles por Servicios , Femenino , Humanos , Masculino , Estudios Retrospectivos , Medición de Riesgo , Factores de Tiempo , Estados Unidos
16.
J Pers Med ; 6(1)2016 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-26861400

RESUMEN

This study aims to confirm the initial pharmacogenetic finding observed within the clinical proof-of-concept trial of an enhanced response to treatment with pomaglumetad methionil (LY2140023 monohydrate) in Caucasian schizophrenia patients homozygous for T/T at single nucleotide polymorphism rs7330461 in the serotonin (5-hydroxytryptamine) 2A receptor gene compared to A/A homozygous patients. The effect of the rs7330461 genotype on the response to pomaglumetad methionil treatment was assessed in three additional clinical trials and in an integrated analysis. Overall, this study includes data from 1115 Caucasian patients for whom genotyping information for rs7330461 was available, consisting of 513 A/A homozygous, 466 A/T heterozygous and 136 T/T homozygous patients. Caucasian T/T homozygous patients showed significantly (p ≤ 0.05) greater improvement in Positive and Negative Syndrome Scale (PANSS) total scores during treatment with pomaglumetad methionil 40 mg twice daily compared to A/A homozygous patients. Additionally, T/T homozygous patients receiving pomaglumetad methionil had significantly (p ≤ 0.05) greater improvements in PANSS total scores compared to placebo and similar improvements as T/T homozygous patients receiving standard-of-care (SOC) treatment. The findings reported here in conjunction with prior reports show that in Caucasian patients with schizophrenia, the T/T genotype at rs7330461 is consistently associated with an increased treatment response to pomaglumetad methionil compared to the A/A genotype.

17.
Brain Imaging Behav ; 8(2): 183-207, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24092460

RESUMEN

The Genetics Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI), formally established in 2009, aims to provide resources and facilitate research related to genetic predictors of multidimensional Alzheimer's disease (AD)-related phenotypes. Here, we provide a systematic review of genetic studies published between 2009 and 2012 where either ADNI APOE genotype or genome-wide association study (GWAS) data were used. We review and synthesize ADNI genetic associations with disease status or quantitative disease endophenotypes including structural and functional neuroimaging, fluid biomarker assays, and cognitive performance. We also discuss the diverse analytical strategies used in these studies, including univariate and multivariate analysis, meta-analysis, pathway analysis, and interaction and network analysis. Finally, we perform pathway and network enrichment analyses of these ADNI genetic associations to highlight key mechanisms that may drive disease onset and trajectory. Major ADNI findings included all the top 10 AD genes and several of these (e.g., APOE, BIN1, CLU, CR1, and PICALM) were corroborated by ADNI imaging, fluid and cognitive phenotypes. ADNI imaging genetics studies discovered novel findings (e.g., FRMD6) that were later replicated on different data sets. Several other genes (e.g., APOC1, FTO, GRIN2B, MAGI2, and TOMM40) were associated with multiple ADNI phenotypes, warranting further investigation on other data sets. The broad availability and wide scope of ADNI genetic and phenotypic data has advanced our understanding of the genetic basis of AD and has nominated novel targets for future studies employing next-generation sequencing and convergent multi-omics approaches, and for clinical drug and biomarker development.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Disfunción Cognitiva/genética , Disfunción Cognitiva/fisiopatología , Enfermedad de Alzheimer/psicología , Biomarcadores/metabolismo , Cognición/fisiología , Disfunción Cognitiva/psicología , Humanos , Neuroimagen/métodos , Fenotipo
18.
Biol Psychiatry ; 73(6): 546-54, 2013 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-23158458

RESUMEN

BACKGROUND: The 5-hydroxytryptamine 2A receptor, encoded by HTR2A, is a major postsynaptic target for serotonin in the human brain and a therapeutic drug target. Despite hundreds of genetic associations investigating HTR2A polymorphisms in neuropsychiatric disorders and therapies, the role of genetic HTR2A variability in health and disease remains uncertain. METHODS: To discover and characterize regulatory HTR2A variants, we sequenced whole transcriptomes from 10 human brain regions with massively parallel RNA sequencing and measured allelic expression of multiple HTR2A messenger (m)RNA transcript variants. Following discovery of functional variants, we further characterized their impact on genetic expression in vitro. RESULTS: Three polymorphisms modulate the use of novel alternative exons and untranslated regions (UTRs), changing expression of RNA and protein. The frequent promoter variant rs6311, widely implicated in human neuropsychiatric disorders, decreases usage of an upstream transcription start site encoding a longer 5'UTR with greater translation efficiency. rs76665058, located in an extended 3'UTR and unique to individuals of African descent, modulates allelic HTR2A mRNA expression. The third single nucleotide polymorphism, unannotated and present in only a single subject, directs alternative splicing of exon 2. Targeted analysis of HTR2A in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study reveals associations between functional variants and depression severity or citalopram response. CONCLUSIONS: Regulatory polymorphisms modulate HTR2A mRNA expression in an isoform-specific manner, directing the usage of novel untranslated regions and alternative exons. These results provide a foundation for delineating the role of HTR2A and serotonin signaling in central nervous system disorders.


Asunto(s)
Corteza Cerebral/metabolismo , Regulación de la Expresión Génica/genética , Variación Genética/genética , Regiones Promotoras Genéticas/genética , Receptor de Serotonina 5-HT2A/biosíntesis , Alelos , Ensayos Clínicos como Asunto , Depresión/tratamiento farmacológico , Depresión/genética , Exones/genética , Humanos , Metilación , Polimorfismo de Nucleótido Simple/genética , Isoformas de Proteínas/biosíntesis , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Transcriptoma/genética , Regiones no Traducidas/genética
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