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BACKGROUND: On June 1, 2021, Vermont repealed all criminal penalties for possessing 224 milligrams or less of buprenorphine. We examined the potential impact of decriminalization with a survey of Vermont clinicians who prescribed buprenorphine within the past year. METHODS: All 638 Vermont clinicians with a waiver to prescribe buprenorphine were emailed the survey by Vermont Department of Health; 117 responded. We estimated the prevalence of the following four outcomes, for all responding clinicians and stratified by clinician demographics and practice characteristics: awareness of decriminalization, beliefs about the effects of decriminalization, support for decriminalization, and changes in practice resulting from decriminalization. RESULTS: 72 (62%) prescribers correctly stated that Vermont does not have criminal penalties for buprenorphine possession. 107 (91%) support decriminalization. 56 (48%) believe that, because buprenorphine is decriminalized, their patients are more likely to give, sell, or trade the buprenorphine that is prescribed to them to someone else. However, only 5 providers (4%) said they now prescribe to fewer patients. CONCLUSION: The great majority of Vermont clinicians who prescribe buprenorphine support its decriminalization and have not changed their prescribing practices because of decriminalization.
In 2021, Vermont repealed criminal penalties for buprenorphine possession.We surveyed Vermont (n = 117) buprenorphine prescribers about decriminalization.91% of providers support decriminalization.48% of providers believe decriminalization will increase diversion of medications.Only 4% of providers prescribe to fewer patients because of decriminalization.
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Buprenorfina , Trastornos Relacionados con Opioides , Humanos , Buprenorfina/uso terapéutico , Vermont , Encuestas y Cuestionarios , Pautas de la Práctica en Medicina , Trastornos Relacionados con Opioides/tratamiento farmacológico , Tratamiento de Sustitución de OpiáceosRESUMEN
OBJECTIVES: Amplitude integrated electroencephalography (aEEG) is a mainstay of care in neonatal ICUs; however, knowledge gaps exist in relation to its accuracy for identifying seizures in older children. We aimed to review the diagnostic accuracy of existing neonatal seizure detection criteria for seizure detection in older children in hospital. DESIGN: Retrospective study. SETTING: PICU/Neurophysiology Department in Dublin. PATIENTS: One hundred twenty patients (2 mo to 16 yr old) were chosen from a database of formal 10-20 system, 21-lead electroencephalography recordings (2012-2020), comprising 30 studies with seizures, 90 without. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Electroencephalography studies containing electrographic seizures (ESzs) were annotated to describe number, duration, distribution, and spread. Two-channel aEEG (using leads C3-P3, C4-P4) recordings were generated and independently reviewed by a professional specialist in clinical neurophysiology blinded to outcome and without reference to the raw electroencephalography trace. Logistic regression was used to identify factors associated with correct seizure identification on aEEG. Median patient age was 6.1 years. Abnormal recordings featured 123 seizures. Status epilepticus (SE) was evident by electroencephalography in 10 cases. Using neonatal criteria, aEEG had a sensitivity of 70% and negative predictive value of 90% for identifying any ESz. Accurate detection of individual seizures was diminished when seizures were very short or occurred during waking. Sensitivity for individual seizures was 81% when seizures less than 1 minute were excluded. aEEG correctly identified SE in 70% of the 10 cases, although ESz were confirmed to be present in 80% of this subpopulation. CONCLUSIONS: aEEG criteria for neonatal seizure identification can be applied with caution to older children and should be supplemented by formal electroencephalography. Seizure identification is better for longer seizures and those arising from sleep. SE is not always recognized by aEEG among older children.
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Epilepsia , Enfermedades del Recién Nacido , Estado Epiléptico , Niño , Recién Nacido , Humanos , Adolescente , Estudios Retrospectivos , Convulsiones/diagnóstico , Electroencefalografía , Unidades de Cuidado Intensivo NeonatalRESUMEN
Huntington disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. Therapeutics that lower HTT have shown preclinical promise and are being evaluated in clinical trials. However, clinical assessment of brain HTT lowering presents challenges. We have reported that mutant HTT (mHTT) in the CSF of HD patients correlates with clinical measures, including disease burden as well as motor and cognitive performance. We have also shown that lowering HTT in the brains of HD mice results in correlative reduction of mHTT in the CSF, prompting the use of this measure as an exploratory marker of target engagement in clinical trials. In this study, we investigate the mechanisms of mHTT clearance from the brain in adult mice of both sexes to elucidate the significance of therapy-induced CSF mHTT changes. We demonstrate that, although neurodegeneration increases CSF mHTT concentrations, mHTT is also present in the CSF of mice in the absence of neurodegeneration. Importantly, we show that secretion of mHTT from cells in the CNS followed by glymphatic clearance from the extracellular space contributes to mHTT in the CSF. Furthermore, we observe secretion of wild type HTT from healthy control neurons, suggesting that HTT secretion is a normal process occurring in the absence of pathogenesis. Overall, our data support both passive release and active clearance of mHTT into CSF, suggesting that its treatment-induced changes may represent a combination of target engagement and preservation of neurons.SIGNIFICANCE STATEMENT: Changes in CSF mutant huntingtin (mHTT) are being used as an exploratory endpoint in HTT lowering clinical trials for the treatment of Huntington disease (HD). Recently, it was demonstrated that intrathecal administration of a HTT lowering agent leads to dose-dependent reduction of CSF mHTT in HD patients. However, little is known about how HTT, an intracellular protein, reaches the extracellular space and ultimately the CSF. Our findings that HTT enters CSF by both passive release and active secretion followed by glymphatic clearance may have significant implications for interpretation of treatment-induced changes of CSF mHTT in clinical trials for HD.
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Química Encefálica , Proteína Huntingtina/líquido cefalorraquídeo , Enfermedad de Huntington/líquido cefalorraquídeo , Animales , Astrocitos/metabolismo , Biomarcadores/líquido cefalorraquídeo , Femenino , Sistema Glinfático/metabolismo , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Masculino , Ratones , Ratones Transgénicos , Mutación , Neuronas/metabolismo , Expansión de Repetición de TrinucleótidoRESUMEN
BACKGROUND: Juvenile-onset Huntington's disease (JOHD) is a rare and particularly devastating form of Huntington's disease (HD) for which clinical diagnosis is challenging and robust outcome measures are lacking. Neurofilament light protein (NfL) in plasma has emerged as a prognostic biomarker for adult-onset HD. METHODS: We performed a retrospective analysis of samples and data collected between 2009 and 2020 from the Kids-HD and Kids-JHD studies. Plasma samples from children and young adults with JOHD, premanifest HD (preHD) mutation carriers, and age-matched controls were used to quantify plasma NfL concentrations using ultrasensitive immunoassay. RESULTS: We report elevated plasma NfL concentrations in JOHD and premanifest HD mutation-carrying children. In pediatric HD mutation carriers who were within 20 years of their predicted onset and patients with JOHD, plasma NfL level was associated with caudate and putamen volumes. CONCLUSIONS: Quantifying plasma NfL concentration may assist clinical diagnosis and therapeutic trial design in the pediatric population. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
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Enfermedad de Huntington , Biomarcadores , Niño , Progresión de la Enfermedad , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/genética , Filamentos Intermedios/metabolismo , Proteínas de Neurofilamentos , Estudios Retrospectivos , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral , Adulto JovenRESUMEN
BACKGROUND: Remote monitoring of Huntington disease (HD) signs and symptoms using digital technologies may enhance early clinical diagnosis and tracking of disease progression, guide treatment decisions, and monitor response to disease-modifying agents. Several recent studies in neurodegenerative diseases have demonstrated the feasibility of digital symptom monitoring. OBJECTIVE: The aim of this study was to evaluate a novel smartwatch- and smartphone-based digital monitoring platform to remotely monitor signs and symptoms of HD. METHODS: This analysis aimed to determine the feasibility and reliability of the Roche HD Digital Monitoring Platform over a 4-week period and cross-sectional validity over a 2-week interval. Key criteria assessed were feasibility, evaluated by adherence and quality control failure rates; test-retest reliability; known-groups validity; and convergent validity of sensor-based measures with existing clinical measures. Data from 3 studies were used: the predrug screening phase of an open-label extension study evaluating tominersen (NCT03342053) and 2 untreated cohorts-the HD Natural History Study (NCT03664804) and the Digital-HD study. Across these studies, controls (n=20) and individuals with premanifest (n=20) or manifest (n=179) HD completed 6 motor and 2 cognitive tests at home and in the clinic. RESULTS: Participants in the open-label extension study, the HD Natural History Study, and the Digital-HD study completed 89.95% (1164/1294), 72.01% (2025/2812), and 68.98% (1454/2108) of the active tests, respectively. All sensor-based features showed good to excellent test-retest reliability (intraclass correlation coefficient 0.89-0.98) and generally low quality control failure rates. Good overall convergent validity of sensor-derived features to Unified HD Rating Scale outcomes and good overall known-groups validity among controls, premanifest, and manifest participants were observed. Among participants with manifest HD, the digital cognitive tests demonstrated the strongest correlations with analogous in-clinic tests (Pearson correlation coefficient 0.79-0.90). CONCLUSIONS: These results show the potential of the HD Digital Monitoring Platform to provide reliable, valid, continuous remote monitoring of HD symptoms, facilitating the evaluation of novel treatments and enhanced clinical monitoring and care for individuals with HD.
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Enfermedad de Huntington , Destreza Motora , Cognición , Estudios Transversales , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/psicología , Enfermedad de Huntington/terapia , Oligonucleótidos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Converging lines of evidence from several models, and post-mortem human brain tissue studies, support the involvement of the kynurenine pathway (KP) in Huntington's disease (HD) pathogenesis. Quantifying KP metabolites in HD biofluids is desirable, both to study pathobiology and as a potential source of biomarkers to quantify pathway dysfunction and evaluate the biochemical impact of therapeutic interventions targeting its components. In a prospective single-site controlled cohort study with standardised collection of cerebrospinal fluid (CSF), blood, phenotypic and imaging data, we used high-performance liquid-chromatography to measure the levels of KP metabolites-tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid and quinolinic acid-in CSF and plasma of 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD). We investigated short-term stability, intergroup differences, associations with clinical and imaging measures and derived sample-size calculation for future studies. Overall, KP metabolites in CSF and plasma were stable over 6 weeks, displayed no significant group differences and were not associated with clinical or imaging measures. We conclude that the studied metabolites are readily and reliably quantifiable in both biofluids in controls and HD gene expansion carriers. However, we found little evidence to support a substantial derangement of the KP in HD, at least to the extent that it is reflected by the levels of the metabolites in patient-derived biofluids.
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Enfermedad de Huntington/sangre , Enfermedad de Huntington/líquido cefalorraquídeo , Quinurenina/sangre , Quinurenina/líquido cefalorraquídeo , Transducción de Señal , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Cromatografía Líquida de Alta Presión , Estudios de Cohortes , Femenino , Humanos , Enfermedad de Huntington/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fenotipo , Estudios ProspectivosRESUMEN
Multiple targeted therapeutics for Huntington's disease are now in clinical trials, including intrathecally delivered compounds. Previous research suggests that CSF dynamics may be altered in Huntington's disease, which could be of paramount relevance to intrathecal drug delivery to the brain. To test this hypothesis, we conducted a prospective cross-sectional study comparing people with early stage Huntington's disease with age- and gender-matched healthy controls. CSF peak velocity, mean velocity and mean flow at the level of the cerebral aqueduct, and sub-arachnoid space in the upper and lower spine, were quantified using phase contrast MRI. We calculated Spearman's rank correlations, and tested inter-group differences with Wilcoxon rank-sum test. Ten people with early Huntington's disease, and 10 controls were included. None of the quantified measures was associated with potential modifiers of CSF dynamics (demographics, osmolality, and brain volumes), or by known modifiers of Huntington's disease (age and HTTCAG repeat length); and no significant differences were found between the two studied groups. While external validation is required, the attained results are sufficient to conclude tentatively that a clinically relevant alteration of CSF dynamics - that is, one that would justify dose-adjustments of intrathecal drugs - is unlikely to exist in Huntington's disease.
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Líquido Cefalorraquídeo/diagnóstico por imagen , Líquido Cefalorraquídeo/fisiología , Enfermedad de Huntington/diagnóstico por imagen , Enfermedad de Huntington/fisiopatología , Imagen por Resonancia Magnética , Estudios Transversales , Femenino , Humanos , Hidrodinámica , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios ProspectivosRESUMEN
Huntington's disease (HD) is a hereditary neurodegenerative condition with no therapeutic intervention known to alter disease progression, but several trials are ongoing and biomarkers of disease progression are needed. Tau is an axonal protein, often altered in neurodegeneration, and recent studies pointed out its role on HD neuropathology. Our goal was to study whether cerebrospinal fluid (CSF) tau is a biomarker of disease progression in HD. After informed consent, healthy controls, pre-symptomatic and symptomatic gene expansion carriers were recruited from two HD clinics. All participants underwent assessment with the Unified HD Rating Scale '99 (UHDRS). CSF was obtained according to a standardized lumbar puncture protocol. CSF tau was quantified using enzyme-linked immunosorbent assay. Comparisons between two groups were tested using ancova. Pearson's correlation coefficients were calculated for disease progression. Significance level was defined as p < 0.05. Seventy-six participants were included in this cross-sectional multicenter international pilot study. Age-adjusted CSF tau was significantly elevated in gene expansion carriers compared with healthy controls (p = 0.002). UHDRS total functional capacity was significantly correlated with CSF tau (r = -0.29, p = 0.004) after adjustment for age, and UHDRS total motor score was significantly correlated with CSF tau after adjustment for age (r = 0.32, p = 0.002). Several UHDRS cognitive tasks were also significantly correlated with CST total tau after age-adjustment. This study confirms that CSF tau concentrations in HD gene mutation carriers are increased compared with healthy controls and reports for the first time that CSF tau concentration is associated with phenotypic variability in HD. These conclusions strengthen the case for CSF tau as a biomarker in HD. In the era of novel targeted approaches to Huntington's disease, reliable biomarkers are needed. We quantified Tau protein, a marker of neuronal death, in cerebrospinal fluid and found it was increased in patients with Huntington's disease and predicted motor, cognitive, and functional disability in patients. It is therefore likely to be a biomarker of disease progression, and possibly of therapeutic response. Read the Editorial Highlight for this article on page 9.
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Enfermedad de Huntington/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Adulto , Anciano , Biomarcadores/líquido cefalorraquídeo , Estudios Transversales , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Heterocigoto , Humanos , Enfermedad de Huntington/fisiopatología , Masculino , Persona de Mediana Edad , Fenotipo , Proyectos Piloto , Valor Predictivo de las Pruebas , Adulto JovenRESUMEN
INTRODUCTION: Medications for opioid use disorder (MOUD), including buprenorphine, reduce overdose risk and improve outcomes for individuals with opioid use disorder (OUD). However, historically, most non-opioid treatment program (non-OTP) specialty substance use treatment programs have not offered buprenorphine. Understanding barriers to offering buprenorphine in specialty substance use treatment settings is critical for expanding access to buprenorphine. This study aims to examine program-level attitudinal, financial, and regulatory factors that influence clients' access to buprenorphine in state-licensed non-OTP specialty substance use treatment programs. METHODS: We surveyed leadership from state-licensed non-OTP specialty substance use treatment programs in New Jersey about organizational characteristics, including medications provided on- and off-site and percentage of OUD clients receiving any type of MOUD, and perceived attitudinal, financial, and regulatory barriers and facilitators to buprenorphine. The study estimated prevalence of barriers and compared high MOUD reach (n = 36, 35 %) and low MOUD reach (n = 66, 65 %) programs. RESULTS: Most responding organizations offered at least one type of MOUD either on- or off-site (n = 80, 78 %). However, 71 % of organizations stated that fewer than a quarter of their clients with OUD use any type of MOUD. Endorsement of attitudinal, financial, and institutional barriers to buprenorphine were similar among high and low MOUD reach programs. The most frequently endorsed government actions suggested to increase use of buprenorphine were facilitating access to long-acting buprenorphine (n = 95, 96 %), education and stigma reduction for clients and families (n = 95, 95 %), and financial assistance to clients to pay for medications (n = 90, 90 %). CONCLUSIONS: Although non-OTP specialty substance use programs often offer clients access to MOUD, including buprenorphine, most OUD clients do not actually receive MOUD. Buprenorphine uptake in these settings may require increased financial support for programs and clients, more robust education and training for providers, and efforts to reduce the stigma associated with medication among clients and their families.
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Buprenorfina , Liderazgo , Concesión de Licencias , Tratamiento de Sustitución de Opiáceos , Trastornos Relacionados con Opioides , Pautas de la Práctica en Medicina , Centros de Tratamiento de Abuso de Sustancias , Femenino , Humanos , Masculino , Actitud del Personal de Salud , Buprenorfina/administración & dosificación , Buprenorfina/economía , Buprenorfina/provisión & distribución , Buprenorfina/uso terapéutico , Estudios Transversales , Prescripciones de Medicamentos/estadística & datos numéricos , Personal de Salud/educación , Internet , Servicios de Salud Mental , New Jersey , Tratamiento de Sustitución de Opiáceos/economía , Tratamiento de Sustitución de Opiáceos/estadística & datos numéricos , Trastornos Relacionados con Opioides/complicaciones , Trastornos Relacionados con Opioides/tratamiento farmacológico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Evaluación de Programas y Proyectos de Salud , Autoinforme , Estatus Social , Centros de Tratamiento de Abuso de Sustancias/economía , Centros de Tratamiento de Abuso de Sustancias/legislación & jurisprudencia , Centros de Tratamiento de Abuso de Sustancias/organización & administración , Centros de Tratamiento de Abuso de Sustancias/estadística & datos numéricos , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/etiología , Síndrome de Abstinencia a Sustancias/prevención & control , Encuestas y CuestionariosRESUMEN
Huntington's disease is an inherited neurodegenerative disorder for which a wide range of disease-modifying therapies are in development and the availability of biomarkers to monitor treatment response is essential for the success of clinical trials. Baseline levels of neurofilament light chain in CSF and plasma have been shown to be effective in predicting clinical disease status, subsequent clinical progression and brain atrophy. The identification of further sensitive prognostic fluid biomarkers is an active research area, and total-Tau and YKL-40 levels have been shown to be increased in CSF from Huntington's disease mutation carriers. The use of readouts with clinical utility in the preclinical assessment of potential therapeutics should aid in the translation of new treatments. Here, we set out to determine how the concentrations of these three proteins change in plasma and CSF with disease progression in representative, well-established mouse models of Huntington's disease. Plasma and CSF were collected throughout disease progression from R6/2 transgenic mice with CAG repeats of 200 or 90 codons (R6/2:Q200 and R6/2:Q90), zQ175 knock-in mice and YAC128 transgenic mice, along with their respective wild-type littermates. Neurofilament light chain and total-Tau concentrations were quantified in CSF and plasma using ultrasensitive single-molecule array (Quanterix) assays, and a novel Quanterix assay was developed for breast regression protein 39 (mouse homologue of YKL-40) and used to quantify breast regression protein 39 levels in plasma. CSF levels of neurofilament light chain and plasma levels of neurofilament light chain and breast regression protein 39 increased in wild-type biofluids with age, whereas total-Tau remained constant. Neurofilament light chain and breast regression protein 39 were elevated in the plasma and CSF from Huntington's disease mouse models, as compared with wild-type littermates, at presymptomatic stages, whereas total-Tau was only increased at the latest disease stages analysed. Levels of biomarkers that had been measured in the same CSF or plasma samples taken at the latest stages of disease were correlated. The demonstration that breast regression protein 39 constitutes a robust plasma biomarker in Huntington's disease mouse models supports the further investigation of YKL-40 as a CSF biomarker for Huntington's disease mutation carriers. Neurofilament light chain and Tau are considered markers of neuronal damage, and breast regression protein 39 is a marker of inflammation; the similarities and differences in the levels of these proteins between mouse models may provide future insights into their underlying pathology. These data will facilitate the use of fluid biomarkers in the preclinical assessment of therapeutic agents for Huntington's disease, providing readouts with direct relevance to clinical trials.
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Importance: Rates of overdose deaths involving synthetic opioids remain high, increasingly involve stimulants combined with opioids, and are increasing rapidly in racially and ethnically minoritized communities, yet little is known about access to harm reduction and treatment services in these groups. Objective: To characterize access and barriers to harm reduction and treatment in a racially and ethnically diverse population of people who use drugs. Design, Setting, and Participants: A cross-sectional telephone survey of people recruited from 39 treatment, harm reduction, and social service organizations in Milwaukee County, Wisconsin; Flint and Detroit, Michigan; and statewide in New Jersey was conducted from January 30 to July 28, 2023. Adults who used cocaine, methamphetamine, or opioids in the past 30 days called a study hotline and completed an interview in English or Spanish. Exposures: Overdose experience, drug types used (opioids only, stimulants only, and polysubstance), and social risk factors (eg, financial instability and criminal legal involvement). Main Outcomes and Measures: Recent use of any harm reduction services, fentanyl test strips, naloxone possession, treatment, and self-reported barriers to services. Results: Of the total sample of 1240 adults, 486 (39.2%) were Black non-Hispanic, 183 (14.8%) were Hispanic, and 464 (37.4%) were White non-Hispanic. In the past 30 days, 826 individuals (66.6%) were polysubstance users, 135 (10.9%) used only opioids, and 279 (22.5%) used only stimulants. A total of 349 respondents (28.1%) experienced a prior-year overdose. Compared with those without a prior-year overdose, people with overdose were more likely to possess naloxone (80.7% vs 68.2%; P < .001), possess fentanyl test strips (36.8% vs 23.5%; P < .001), and use harm reduction services (63.4% vs 53.0%; P = .003), while differences in treatment use were nonsignificant (52.0% vs 46.6%; P = .24). Among stimulant-only users, 51.4% possessed naloxone compared with 77.3% of opioid-only users (P < .001) and 77.6% of polysubstance users (P < .001), with similar disparities in fentanyl test strip possession. Conclusions and Relevance: In this cross-sectional study of people who used drugs in the past 30 days, findings highlighted low use of harm reduction and treatment services among people who use stimulants. Additional communication regarding their importance may help increase the use of the services amidst a rapidly changing drug supply.
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Sobredosis de Droga , Reducción del Daño , Humanos , Femenino , Masculino , Adulto , Estudios Transversales , Sobredosis de Droga/prevención & control , Persona de Mediana Edad , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Adulto Joven , Naloxona/uso terapéutico , Trastornos Relacionados con Sustancias , Factores de Riesgo , Wisconsin , New Jersey , Michigan , Analgésicos Opioides/uso terapéuticoRESUMEN
Juvenile Huntington's disease (JHD) is rare. In the first decade of life speech difficulties, rigidity, and dystonia are common clinical motor symptoms, whereas onset in the second decade motor symptoms may sometimes resemble adult-onset Huntington's disease (AOHD). Cognitive decline is mostly detected by declining school performances. Behavioral symptoms in general do not differ from AOHD but may be confused with autism spectrum disorder or attention deficit hyperactivity disorder and lead to misdiagnosis and/or diagnostic delay. JHD specific features are epilepsy, ataxia, spasticity, pain, itching, and possibly liver steatosis. Disease progression of JHD is faster compared to AOHD and the disease duration is shorter, particularly in case of higher CAG repeat lengths. The diagnosis is based on clinical judgement in combination with a positive family history and/or DNA analysis after careful consideration. Repeat length in JHD is usuallyâ>â55 and caused by anticipation, usually via paternal transmission. There are no pharmacological and multidisciplinary guidelines for JHD treatment. Future perspectives for earlier diagnosis are better diagnostic markers such as qualitative MRI and neurofilament light in serum.
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Enfermedad de Huntington , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/genética , Adolescente , Niño , Progresión de la Enfermedad , Edad de InicioRESUMEN
Neurofilament light chain is an established marker of neuroaxonal injury that is elevated in CSF and blood across various neurological diseases. It is increasingly used in clinical practice to aid diagnosis and monitor progression and as an outcome measure to assess safety and efficacy of disease-modifying therapies across the clinical translational neuroscience field. Quantitative methods for neurofilament light chain in human biofluids have relied on immunoassays, which have limited capacity to describe the structure of the protein in CSF and how this might vary in different neurodegenerative diseases. In this study, we characterized and quantified neurofilament light chain species in CSF across neurodegenerative and neuroinflammatory diseases and healthy controls using targeted mass spectrometry. We show that the quantitative immunoprecipitation-tandem mass spectrometry method developed in this study strongly correlates to single-molecule array measurements in CSF across the broad spectrum of neurodegenerative diseases and was replicable across mass spectrometry methods and centres. In summary, we have created an accurate and cost-effective assay for measuring a key biomarker in translational neuroscience research and clinical practice, which can be easily multiplexed and translated into clinical laboratories for the screening and monitoring of neurodegenerative disease or acute brain injury.
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BACKGROUND: In July 2021, Vermont removed all criminal penalties for possessing 224mg or less of buprenorphine. METHODS: Vermont residents (N=474) who used illicit opioid drugs or received treatment for opioid use disorder in the past 90 days were recruited for a mixed-methods survey on the health and criminal legal effects of decriminalization. Topics assessed included: motivations for using non-prescribed buprenorphine, awareness of and support for decriminalization, and criminal legal system experiences involving buprenorphine. We examined the frequencies of quantitative measures and qualitatively summarized themes from free-response questions. RESULTS: Three-quarters of respondents (76%) reported lifetime use of non-prescribed buprenorphine. 80% supported decriminalization, but only 28% were aware buprenorphine was decriminalized in Vermont. Respondents described using non-prescribed buprenorphine to alleviate withdrawal symptoms and avoid use of other illicit drugs. 18% had been arrested while in buprenorphine, with non-White respondents significantly more likely to report such arrests (15% v 33%, p<0.001). CONCLUSION: Decriminalization of buprenorphine may reduce unnecessary criminal legal system involvement, but its health impact was limited by low awareness at the time of our study.
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Buprenorfina , Drogas Ilícitas , Trastornos Relacionados con Opioides , Humanos , Analgésicos Opioides/uso terapéutico , Buprenorfina/uso terapéutico , Vermont/epidemiología , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/epidemiología , Actitud , Tratamiento de Sustitución de OpiáceosRESUMEN
BACKGROUND: Alzheimer's disease (AD) is characterized by the intra- and extracellular accumulation of amyloid-ß (Aß) peptides. How Aß aggregates perturb the proteome in brains of patients and AD transgenic mouse models, remains largely unclear. State-of-the-art mass spectrometry (MS) methods can comprehensively detect proteomic alterations, providing relevant insights unobtainable with transcriptomics investigations. Analyses of the relationship between progressive Aß aggregation and protein abundance changes in brains of 5xFAD transgenic mice have not been reported previously. METHODS: We quantified progressive Aß aggregation in hippocampus and cortex of 5xFAD mice and controls with immunohistochemistry and membrane filter assays. Protein changes in different mouse tissues were analyzed by MS-based proteomics using label-free quantification; resulting MS data were processed using an established pipeline. Results were contrasted with existing proteomic data sets from postmortem AD patient brains. Finally, abundance changes in the candidate marker Arl8b were validated in cerebrospinal fluid (CSF) from AD patients and controls using ELISAs. RESULTS: Experiments revealed faster accumulation of Aß42 peptides in hippocampus than in cortex of 5xFAD mice, with more protein abundance changes in hippocampus, indicating that Aß42 aggregate deposition is associated with brain region-specific proteome perturbations. Generating time-resolved data sets, we defined Aß aggregate-correlated and anticorrelated proteome changes, a fraction of which was conserved in postmortem AD patient brain tissue, suggesting that proteome changes in 5xFAD mice mimic disease-relevant changes in human AD. We detected a positive correlation between Aß42 aggregate deposition in the hippocampus of 5xFAD mice and the abundance of the lysosome-associated small GTPase Arl8b, which accumulated together with axonal lysosomal membranes in close proximity of extracellular Aß plaques in 5xFAD brains. Abnormal aggregation of Arl8b was observed in human AD brain tissue. Arl8b protein levels were significantly increased in CSF of AD patients. CONCLUSIONS: We report a comprehensive biochemical and proteomic investigation of hippocampal and cortical brain tissue derived from 5xFAD transgenic mice, providing a valuable resource to the neuroscientific community. We identified Arl8b, with significant abundance changes in 5xFAD and AD patient brains. Arl8b might enable the measurement of progressive lysosome accumulation in AD patients and have clinical utility as a candidate biomarker.
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Enfermedad de Alzheimer , Ratones , Humanos , Animales , Enfermedad de Alzheimer/metabolismo , Proteoma/metabolismo , Proteómica , Péptidos beta-Amiloides/metabolismo , Ratones Transgénicos , Encéfalo/metabolismo , Biomarcadores/metabolismo , Modelos Animales de EnfermedadRESUMEN
The pathophysiology of stress urinary incontinence (SUI) is multifactorial and evidence supports a critical role of pregnancy and vaginal delivery. This review dissects epidemiologic literature to determine the weight of evidence on the role of advanced maternal age (AMA) as a risk factor for the development of subsequent or persistent SUI. We conducted a Medline search using the keywords postpartum, SUI, maternal age, pregnancy, and incontinence. The published literature was critically analyzed. Evidence supports that childbirth trauma contributes to the development and severity of SUI. Yet, there is contradicting evidence as to whether AMA increases the risk. AMA clearly represents an independent risk factor for postpartum SUI. However, long-term studies did not confirm this observation. Whether this finding is suggestive of a true biologic signal that is lost with competing risk factors over time warrants further research.
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Edad Materna , Periodo Posparto , Incontinencia Urinaria de Esfuerzo/epidemiología , Adulto , Parto Obstétrico/efectos adversos , Femenino , Humanos , Parto , Embarazo , Factores de RiesgoRESUMEN
Lumbar puncture (LP) has become increasingly common for people with Huntington's disease (HD) both to administer intrathecal investigational medicinal products and to collect cerebrospinal fluid to develop biological markers to track disease stage and progression. We aimed to investigate the safety profile of LP in people with HD, building on a recently published work by increasing the sample size and more specifically, increasing the representation of the premanifest population and healthy controls. We conducted a multi-study cross-sectional analysis including eligible participants from the HDClarity (304 Huntington's disease gene expansion carriers and 91 controls) and HD-YAS studies (54 premanifest and 48 controls), enrolled between February 2016 and September 2019. We investigated the odds of any adverse events, headaches, and back pain independently. Intergroup comparisons and adjusted event odds were derived using hierarchical logistic regressions. A total of 669 LP procedures involving 497 participants were included in this analysis. There were 184 (27.5%) LP procedures associated with one or more adverse events. The two most common adverse events were: post LP headache and back pain. Younger age and female gender were found to be associated with a higher risk of developing adverse events. There was no difference in the rate of adverse events between the disease subgroups after adjusting for covariates such as age and gender. Our results suggest that the LP is safe and tolerable in premanifest and manifest HD subjects, providing useful reassurance about the procedure to the HD community.
Asunto(s)
Enfermedad de Huntington , Humanos , Femenino , Enfermedad de Huntington/genética , Estudios Transversales , Punción Espinal , Heterocigoto , Biomarcadores , Progresión de la EnfermedadRESUMEN
Proton magnetic resonance spectroscopy is a non-invasive method of exploring cerebral metabolism. In Huntington's disease, altered proton magnetic resonance spectroscopy-determined concentrations of several metabolites have been described; however, findings are often discrepant and longitudinal studies are lacking. Proton magnetic resonance spectroscopy metabolites may represent a source of biomarkers, thus their relationship with established markers of disease progression require further exploration to assess prognostic value and elucidate pathways associated with neurodegeneration. In a prospective single-site controlled cohort study with standardized collection of CSF, blood, phenotypic and volumetric imaging data, we used 3â T proton magnetic resonance spectroscopy in conjunction with the linear combination of model spectra method to quantify seven metabolites (total n-acetylaspartate, total creatine, total choline, myo-inositol, GABA, glutamate and glutathione) in the putamen of 59 participants at baseline (15 healthy controls, 15 premanifest and 29 manifest Huntington's disease gene expansion carriers) and 48 participants at 2-year follow-up (12 healthy controls, 13 premanifest and 23 manifest Huntington's disease gene expansion carriers). Intergroup differences in concentration and associations with CSF and plasma biomarkers; including neurofilament light chain and mutant Huntingtin, volumetric imaging markers; namely whole brain, caudate, grey matter and white matter volume, measures of disease progression and cognitive decline, were assessed cross-sectionally using generalized linear models and partial correlation. We report no significant groupwise differences in metabolite concentration at baseline but found total creatine and total n-acetylaspartate to be significantly reduced in manifest compared with premanifest participants at follow-up. Additionally, total creatine and myo-inositol displayed significant associations with reduced caudate volume across both time points in gene expansion carriers. Although relationships were observed between proton magnetic resonance spectroscopy metabolites and biofluid measures, these were not consistent across time points. To further assess prognostic value, we examined whether baseline proton magnetic resonance spectroscopy values, or rate of change, predicted subsequent change in established measures of disease progression. Several associations were found but were inconsistent across known indicators of disease progression. Finally, longitudinal mixed-effects models revealed glutamine + glutamate to display a slow linear decrease over time in gene expansion carriers. Altogether, our findings show some evidence of reduced total n-acetylaspartate and total creatine as the disease progresses and cross-sectional associations between select metabolites, namely total creatine and myo-inositol, and markers of disease progression, potentially highlighting the proposed roles of neuroinflammation and metabolic dysfunction in disease pathogenesis. However, the absence of consistent group differences, inconsistency between baseline and follow-up, and lack of clear longitudinal change suggests that proton magnetic resonance spectroscopy metabolites have limited potential as Huntington's disease biomarkers.
RESUMEN
Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington's disease (HD), possibly because mutant huntingtin impairs its cortico-striatal transport, contributing to striatal neurodegeneration. The BDNF trophic pathway is a therapeutic target, and blood BDNF has been suggested as a potential biomarker for HD, but BDNF has not been quantified in cerebrospinal fluid (CSF) in HD. We quantified BDNF in CSF and plasma in the HD-CSF cohort (20 pre-manifest and 40 manifest HD mutation carriers and 20 age and gender-matched controls) using conventional ELISAs and an ultra-sensitive immunoassay. BDNF concentration was below the limit of detection of the conventional ELISAs, raising doubt about previous CSF reports in neurodegeneration. Using the ultra-sensitive method, BDNF concentration was quantifiable in all samples but did not differ between controls and HD mutation carriers in CSF or plasma, was not associated with clinical scores or MRI brain volumetric measures, and had poor ability to discriminate controls from HD mutation carriers, and premanifest from manifest HD. We conclude that BDNF in CSF and plasma is unlikely to be a biomarker of HD progression and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/sangre , Factor Neurotrófico Derivado del Encéfalo/líquido cefalorraquídeo , Enfermedad de Huntington/sangre , Enfermedad de Huntington/líquido cefalorraquídeo , Adulto , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoensayo , Masculino , Persona de Mediana EdadRESUMEN
Chronic cellular stress associated with neurodegenerative disease can result in the persistence of stress granule (SG) structures, membraneless organelles that form in response to cellular stress. In Huntington's disease (HD), chronic expression of mutant huntingtin generates various forms of cellular stress, including activation of the unfolded protein response and oxidative stress. However, it has yet to be determined whether SGs are a feature of HD neuropathology. We examined the miRNA composition of extracellular vesicles (EVs) present in the cerebrospinal fluid (CSF) of patients with HD and show that a subset of their target mRNAs were differentially expressed in the prefrontal cortex. Of these targets, SG components were enriched, including the SG-nucleating Ras GTPase-activating protein-binding protein 1 (G3BP1). We investigated localization and levels of G3BP1 and found a significant increase in the density of G3BP1-positive granules in the cortex and hippocampus of R6/2 transgenic mice and in the superior frontal cortex of the brains of patients with HD. Intriguingly, we also observed that the SG-associated TAR DNA-binding protein 43 (TDP43), a nuclear RNA/DNA binding protein, was mislocalized to the cytoplasm of G3BP1 granule-positive HD cortical neurons. These findings suggest that G3BP1 SG dynamics may play a role in the pathophysiology of HD.