Summary Background Blood biomarkers of neuronal damage could facilitate clinical management of and therapeutic development for Huntington's disease. We investigated whether neurofilament light ...protein NfL (also known as NF-L) in blood is a potential prognostic marker of neurodegeneration in patients with Huntington's disease. Methods We did a retrospective analysis of healthy controls and carriers of CAG expansion mutations in HTT participating in the 3-year international TRACK-HD study. We studied associations between NfL concentrations in plasma and clinical and MRI neuroimaging findings, namely cognitive function, motor function, and brain volume (global and regional). We used random effects models to analyse cross-sectional associations at each study visit and to assess changes from baseline, with and without adjustment for age and CAG repeat count. In an independent London-based cohort of 37 participants (23 HTT mutation carriers and 14 controls), we further assessed whether concentrations of NfL in plasma correlated with those in CSF. Findings Baseline and follow-up plasma samples were available from 97 controls and 201 individuals carrying HTT mutations. Mean concentrations of NfL in plasma at baseline were significantly higher in HTT mutation carriers than in controls (3·63 SD 0·54 log pg/mL vs 2·68 0·52 log pg/mL, p<0·0001) and the difference increased from one disease stage to the next. At any given timepoint, NfL concentrations in plasma correlated with clinical and MRI findings. In longitudinal analyses, baseline NfL concentration in plasma also correlated significantly with subsequent decline in cognition (symbol-digit modality test r =–0·374, p<0·0001; Stroop word reading r =–0·248, p=0·0033), total functional capacity ( r =–0·289, p=0·0264), and brain atrophy (caudate r =0·178, p=0·0087; whole-brain r =0·602, p<0·0001; grey matter r =0·518, p<0·0001; white matter r =0·588, p<0·0001; and ventricular expansion r =–0·589, p<0·0001). All changes except Stroop word reading and total functional capacity remained significant after adjustment for age and CAG repeat count. In 104 individuals with premanifest Huntington's disease, NfL concentration in plasma at baseline was associated with subsequent clinical onset during the 3-year follow-up period (hazard ratio 3·29 per log pg/mL, 95% CI 1·48–7·34, p=0·0036). Concentrations of NfL in CSF and plasma were correlated in mutation carriers ( r =0·868, p<0·0001). Interpretation NfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington's disease. Funding Medical Research Council, GlaxoSmithKline, CHDI Foundation, Swedish Research Council, European Research Council, Wallenberg Foundation, and Wolfson Foundation.
To provide global, regional, and country-level estimates of diabetes prevalence and health expenditures for 2021 and projections for 2045.
A total of 219 data sources meeting pre-established quality ...criteria reporting research conducted between 2005 and 2020 and representing 215 countries and territories were identified. For countries without data meeting quality criteria, estimates were extrapolated from countries with similar economies, ethnicity, geography and language. Logistic regression was used to generate smoothed age-specific diabetes prevalence estimates. Diabetes-related health expenditures were estimated using an attributable fraction method. The 2021 diabetes prevalence estimates were applied to population estimates for 2045 to project future prevalence.
The global diabetes prevalence in 20–79 year olds in 2021 was estimated to be 10.5% (536.6 million people), rising to 12.2% (783.2 million) in 2045. Diabetes prevalence was similar in men and women and was highest in those aged 75–79 years. Prevalence (in 2021) was estimated to be higher in urban (12.1%) than rural (8.3%) areas, and in high-income (11.1%) compared to low-income countries (5.5%). The greatest relative increase in the prevalence of diabetes between 2021 and 2045 is expected to occur in middle-income countries (21.1%) compared to high- (12.2%) and low-income (11.9%) countries. Global diabetes-related health expenditures were estimated at 966 billion USD in 2021, and are projected to reach 1,054 billion USD by 2045.
Just over half a billion people are living with diabetes worldwide which means that over 10.5% of the world’s adult population now have this condition.
No disease-slowing treatment exists for Huntington's disease, but its monogenic inheritance makes it an appealing candidate for the development of therapies targeting processes close to its genetic ...cause. Huntington's disease is caused by CAG repeat expansions in the HTT gene, which encodes the huntingtin protein; development of therapies to target HTT transcription and the translation of its mRNA is therefore an area of intense investigation. Huntingtin-lowering strategies include antisense oligonucleotides and RNA interference targeting mRNA, and zinc finger transcriptional repressors and CRISPR-Cas9 methods aiming to reduce transcription by targeting DNA. An intrathecally delivered antisense oligonucleotide that aims to lower huntingtin is now well into its first human clinical trial, with other antisense oligonucleotides expected to enter trials in the next 1–2 years and virally delivered RNA interference and zinc finger transcriptional repressors in advanced testing in animal models. Recent advances in the design and delivery of therapies to target HTT RNA and DNA are expected to improve their efficacy, safety, tolerability, and duration of effect in future studies.
Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts ...transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself.
Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic testing, with estimation of years to ...predicted onset, enabling the entire range of disease natural history to be studied. Structural neuroimaging biomarkers show that progressive regional brain atrophy begins many years before the emergence of diagnosable signs and symptoms of HD, and continues steadily during the symptomatic or 'manifest' period. The continued development of functional, neurochemical and other biomarkers raises hopes that these biomarkers might be useful for future trials of disease-modifying therapeutics to delay the onset and slow the progression of HD. Such advances could herald a new era of personalized preventive therapeutics. We describe the natural history of HD, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features. Building on this information, we review recent progress in the development of biomarkers for HD, and potential future roles of these biomarkers in clinical trials.
Huntington's disease is the most frequent autosomal dominant neurodegenerative disorder; however, no disease-modifying interventions are available for patients with this disease. The molecular ...pathogenesis of Huntington's disease is complex, with toxicity that arises from full-length expanded huntingtin and N-terminal fragments of huntingtin, which are both prone to misfolding due to proteolysis; aberrant intron-1 splicing of the HTT gene; and somatic expansion of the CAG repeat in the HTT gene. Potential interventions for Huntington's disease include therapies targeting huntingtin DNA and RNA, clearance of huntingtin protein, DNA repair pathways, and other treatment strategies targeting inflammation and cell replacement. The early termination of trials of the antisense oligonucleotide tominersen suggest that it is time to reflect on lessons learned, where the field stands now, and the challenges and opportunities for the future.
Immune system activation is involved in Huntington's disease (HD) pathogenesis and biomarkers for this process could be relevant to study the disease and characterise the therapeutic response to ...specific interventions. We aimed to study inflammatory cytokines and microglial markers in the CSF of HD patients.
CSF TNF-α, IL-1β, IL-6, IL-8, YKL-40, chitotriosidase, total tau and neurofilament light chain (NFL) from 23 mutation carriers and 14 healthy controls were assayed.
CSF TNF-α and IL-1β were below the limit of detection. Mutation carriers had higher YKL-40 (p = 0.003), chitotriosidase (p = 0.015) and IL-6 (p = 0.041) than controls. YKL-40 significantly correlated with disease stage (p = 0.007), UHDRS total functional capacity score (r = -0.46, p = 0.016), and UHDRS total motor score (r = 0.59, p = 4.5*10-4) after adjustment for age.
YKL-40 levels in CSF may, after further study, come to have a role as biomarkers for some aspects of HD. Further investigation is needed to support our exploratory findings.
Mutated
HTT
, resulting in mutant huntingtin, causes Huntington’s disease. A phase 1–2a trial of intrathecal delivery of an antisense oligonucleotide targeting
HTT
mRNA in 34 persons with ...Huntington’s disease showed a dose-dependent reduction of mutant huntingtin in cerebrospinal fluid and no serious adverse events in those who received the drug.
In chronic neurological conditions, wearable/portable devices have potential as innovative tools to detect subtle early disease manifestations and disease fluctuations for the purpose of clinical ...diagnosis, care and therapeutic development. Huntington's disease (HD) has a unique combination of motor and non-motor features which, combined with recent and anticipated therapeutic progress, gives great potential for such devices to prove useful. The present work aims to provide a comprehensive account of the use of wearable/portable devices in HD and of what they have contributed so far. We conducted a systematic review searching MEDLINE, Embase, and IEEE Xplore. Thirty references were identified. Our results revealed large variability in the types of sensors used, study design, and the measured outcomes. Digital technologies show considerable promise for therapeutic research and clinical management of HD. However, more studies with standardized devices and harmonized protocols are needed to optimize the potential applicability of wearable/portable devices in HD.
•Wearable/portable sensors have been proposed to detect and quantify manifestations of many neurodegenerative diseases.•No systematic review so far has examined their use in Huntington's disease (HD).•This work draws a broad picture of the digital wearable-based landscape in HD.•The utility of wearables in clinical practice and therapeutic research still needs to be proved.•Collaborative efforts are needed to further investigate their clinical use in HD.
PDF
