Papers by Rachael Scahill
The longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington's di... more The longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington's disease (HD)mutant huntingtin (mHTT) and neurofilament light (NfL)are incompletely defined, but could help understand the natural history of the disease and how these biomarkers might help in therapeutic development and the clinic. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), and NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status and subsequent clinical progression and brain atrophy, better than did the rate of change in analytes. Overall NfL was a stronger monitoring and prognostic biomarker for HD than mHTT. Nonetheless, mHTT possesses prognostic value and is a valuable pharmacodynamic marker for huntingtin-lowering trials.
NeuroImage, May 1, 2008
Hippocampal atrophy rates have been used in a number of studies in Alzheimer's disease (AD) to as... more Hippocampal atrophy rates have been used in a number of studies in Alzheimer's disease (AD) to assess disease progression and are being increasingly utilized as an outcome measure in clinical trials of new pharmaceutical agents. Owing to the labor-intensive nature of hippocampal segmentation, more automated approaches are required for such analysis. In this study we compared methods of automatically segmenting the hippocampus (single-person template and template library) on the baseline image in a group of probable AD (n = 36) and control (n = 19) subjects with serial images. Using the method that gave most similar results to manual, three automated methods of calculating change within the hippocampal region were compared: fluid change calculated using (1) Jacobian change or (2) region propagation and (3) boundary shift. Rates were compared with manual measures. We found that segmentation of baseline hippocampus was most accurate using a template library combined with morphological operations (intensity thresholding plus one conditional dilation). This gave a voxel similarity of 0.69 (0.05) and 0.72 (0.06) in controls and probable AD subjects respectively compared with manual measures. Atrophy rates within these regions were most similar to the manual rates using the boundary shift integral (mean difference from manual rate 0.03% (1.29) in controls and 0.48% (2.44) in AD). A template library segmentation approach, together with morphological operations, provides a segmentation accurate enough to quantify relative change over time. The change over time can then be calculated automatically using boundary shift or fluid measures, with boundary shift giving most similar results to manual.
Brain communications, Oct 12, 2022
Proton magnetic resonance spectroscopy is a non-invasive method of exploring cerebral metabolism.... more 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 3 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 crosssectional 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.
Science Translational Medicine, Dec 16, 2020
and Vertex Pharmaceuticals. All honoraria for these consultancies were paid through the offices o... more and Vertex Pharmaceuticals. All honoraria for these consultancies were paid through the offices of UCL Consultants Ltd., a wholly owned subsidiary of University College London. H.Z. has served at scientific advisory boards for Roche Diagnostics, Wave, Samumed, and CogRx; has given lectures in symposia sponsored by Biogen and Alzecure; and is a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. E.J.W. reports grants from Medical Research Council UK, CHDI Foundation, and F. Hoffmann-La Roche Ltd. during the conduct of the study and personal fees from F. Hoffman-
Science Translational Medicine, Sep 12, 2018
Huntington's disease (HD) is a genetic progressive neurodegenerative disorder, caused by a mutati... more Huntington's disease (HD) is a genetic progressive neurodegenerative disorder, caused by a mutation in the HTT gene, for which there is currently no cure. The identification of sensitive indicators of disease progression and therapeutic outcome could help the development of effective strategies for treating HD. Here, we assessed mutant huntingtin (mHTT) and neurofilament light (NfL) protein concentrations in cerebrospinal fluid (CSF) and blood in parallel with clinical evaluation and magnetic resonance imaging (MRI), in premanifest and manifest HD mutation carriers. Among HD mutation carriers, NfL concentrations in plasma and CSF correlated with all non-biofluid measures more closely than did CSF mHTT concentration. Longitudinal analysis over 4-8 weeks showed that CSF mHTT, CSF NfL and plasma NfL concentrations were highly stable within individuals. In our cohort, concentration of CSF mHTT accurately distinguished between controls and HD mutation carriers, while NfL concentration, in both CSF and plasma, was able to segregate premanifest from manifest HD. In silico modeling indicated that mHTT and NfL concentration in biofluids might be among the earliest detectable alterations in HD and sample size prediction suggested that low participant numbers would be needed to incorporate these measures into clinical trials. These findings provide evidence that biofluid concentrations of mHTT and NfL have potential for early and sensitive detection of alterations in HD and could be integrated into both clinical trials and the clinic.
Annals of Neurology, Jan 29, 2003
Regional and global cerebral atrophy are inevitable features of Alzheimer&amp... more Regional and global cerebral atrophy are inevitable features of Alzheimer's disease (AD). We assessed volumes and atrophy rates of brain structures in patients with familial AD during the period that they developed symptoms. Five patients with presymptomatic AD and 20 controls had two or more annual volumetric MRI brain scans. Volumes of brain, ventricles, temporal lobes, hippocampi, and entorhinal cortices (ECs) were measured. Rates of volume change were calculated from serial scans. There were no significant differences in baseline measures of whole brain, temporal lobe, or ventricular volume between patients and controls; averaged volumes of medial temporal lobe structures (both hippocampi and ECs) were 16.6% (95% confidence interval [CI], 3.3-28.0%) lower in patients. Atrophy rates for brain, temporal lobe, hippocampus, and EC were significantly increased in patients compared with controls (p < 0.05). Averaged atrophy rates from both hippocampi and ECs were 5.1% (95% CI, 3.0-7.1%) greater in patients than controls. Linear extrapolation backward suggested medial temporal lobe atrophy commenced 3.5 years (95% CI, 0.7-7.5 years) before onset, when all patients were asymptomatic. We conclude that increased medial temporal lobe atrophy rates are an early and distinguishing feature of AD and that pathological atrophy probably is occurring several years before the onset of symptoms.
Neurobiology of Aging, Nov 1, 2007
We describe a method of automatically calculating hippocampal atrophy rates on T1-weighted MR ima... more We describe a method of automatically calculating hippocampal atrophy rates on T1-weighted MR images without manual delineation of hippocampi. This method was applied to a group of Alzheimer's disease (AD) (n = 36) and control (n = 19) subjects and compared with manual methods (manual segmentation of baseline and repeat-image hippocampi) and semi-automated methods (manual segmentation of baseline hippocampi only). In controls, mean (S.D.) atrophy rates for manual, semi-automated, and automated methods were 18.1 (53.5), 15.3 (50.2) and 11.3 (50.4) mm 3 loss per year, respectively. In AD patients these rates were 174.6 (106.5) 159.4 (101.2) and 172.1 (123.1) mm 3 loss per year, respectively. The automated method was a significant predictor of disease (p = 0.001) and gave similar group discrimination compared with both semi-automated and manual methods. The automated hippocampal analysis in this small study took approximately 20 min per hippocampal pair on a 3.4 GHz Intel Xeon server, whereas manual delineation of each hippocampal pair took approximately 90 min of operator-intensive labour. This method may be useful diagnostically or in studies where analysis of many scans may be required.
Neurology, Jan 24, 2018
Neurofilament light (NfL) protein in blood plasma has been proposed as a prognostic biomarker of ... more Neurofilament light (NfL) protein in blood plasma has been proposed as a prognostic biomarker of neurodegeneration in a number of conditions, including Huntington disease (HD). This study investigates the regional distribution of NfL-associated neural pathology in HD gene expansion carriers. We examined associations between NfL measured in plasma and regionally specific atrophy in cross-sectional (n = 198) and longitudinal (n = 177) data in HD gene expansion carriers from the international multisite TRACK-HD study. Using voxel-based morphometry, we measured associations between baseline NfL levels and both baseline gray matter and white matter volume; and longitudinal change in gray matter and white matter over the subsequent 3 years in HD gene expansion carriers. After controlling for demographics, associations between increased NfL levels and reduced brain volume were seen in cortical and subcortical gray matter and within the white matter. After also controlling for known predictors of disease progression (age and CAG repeat length), associations were limited to the caudate and putamen. Longitudinally, NfL predicted subsequent occipital gray matter atrophy and widespread white matter reduction, both before and after correction for other predictors of disease progression. These findings highlight the value of NfL as a dynamic marker of brain atrophy and, more generally, provide further evidence of the strong association between plasma NfL level, a candidate blood biomarker, and pathologic neuronal change. From the Huntington's Disease Research Centre (E.
Scientific Reports, Mar 9, 2018
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by CAG repeat... more Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by CAG repeat expansions in HTT encoding mutant huntingtin protein 1 . The pathogenesis of HD is multifactorial and includes synaptic dysfunction 2 and activation of the innate immune system, most likely due to a direct effect of mutant huntingtin in myeloid cells . We previously showed that cytokines and chemokines 6 are increased in plasma in HD mutation carriers and that CSF in HD contains increased levels of the microglia-associated proteins chitotriosidase and YKL40, with the latter independently associated with the severity of motor symptoms 7 . Modulating the immune system has the potential to offer therapeutic benefit in HD 8 and one trial of a putative microglial-modulating agent (laquinimod) is currently underway . Neurogranin is a postsynaptic protein that regulates the availability of calmodulin 11 that has been proposed as a synaptic function biomarker . Neurogranin has been shown to be increased in CSF in Alzheimer's disease (AD) but not in other neurodegenerative conditions such as frontotemporal dementia (FTD), Lewy body disease, Parkinson's disease (PD), progressive supranuclear palsy and multiple system atrophy 14 . There is evidence that synaptic dysfunction contributes to HD pathology , and a whole-brain gene expression study in post-mortem HD patient brains identified that NRGN, encoding neurogranin, was among the most robustly downregulated genes in HD caudate compared to controls . However, it has not previously been quantified in CSF in HD. Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor expressed by myeloid cells including monocytes, macrophages and microglia whose activation is inhibitory to the immune response . Missense mutations in TREM2 are associated with CNS disease 20 and single-nucleotide TREM2 polymorphisms have been reported as genetic modifiers of AD 21 , amyotrophic lateral sclerosis 22 , PD and FTD 23 . Soluble TREM2 is quantifiable in CSF and has been reported as elevated in AD , and in multiple sclerosis, where it normalised upon immunomodulatory treatment 26 . While TREM2 has not specifically been linked to the pathobiology of HD, dysfunction of myeloid cells due to cell-autonomous expression of mutant huntingtin is a well-described feature of the disease 5 , and other microglial-associated proteins have shown disease-related alterations in HD patient CSF 7 .
Lancet Neurology, Jul 1, 2022
Journal of Neurology, Neurosurgery, and Psychiatry, Dec 1, 2009
Unbiased longitudinal studies are needed to understand the distributed neurodegenerative changes ... more Unbiased longitudinal studies are needed to understand the distributed neurodegenerative changes of Huntington's disease (HD). They may also provide tools for assessing disease-modifying interventions. The authors investigated the progression of regional atrophy in premanifest and early HD compared with controls.
Scientific Reports, Nov 1, 2022
Lumbar puncture (LP) has become increasingly common for people with Huntington's disease (HD) bot... more 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.
Connectomics can be used to investigate functional brain networks in neurodegenerative diseases i... more Connectomics can be used to investigate functional brain networks in neurodegenerative diseases including Huntington's disease (HD). In this developing field, different connectome construction strategies have emerged in parallel. However, there is a need to understand the influences of different strategies on subsequent analyses when constructing a connectome. This study systematically compares connectome construction strategies based on their biological relevance to functional networks in neurodegeneration. We asked which functional connectome construction strategy was best able to discriminate HD gene carriers from healthy controls, and how such a strategy affected modular organization of the network. The major factors compared were principal component-based correction versus wavelet decomposition for physiological noise correction, the type of parcellation atlas (functional, structural and multi-modal), weighted versus binarized networks, and unthresholded versus proportionally thresholded networks. We found that principal component-based correction generated the most discriminatory connectomes, while binarization and proportional thresholding did not increase discrimination between HD gene carriers and healthy controls. When a functional parcellation atlas was used, the highest discrimination rates were obtained. We observed that the group differences in modular organization of the functional connectome were greatly affected by binarization and thresholding, showing no consistent pattern of modularity. This study suggests that functional connectome construction strategies using principal component-based correction and weighted unthresholded connectivity matrices may outperform other strategies.
Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF ... more 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. 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) were quantified 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. 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.
Background Huntington’s disease (HD) is a progressive neurodegenerative disorder where there is a... more Background Huntington’s disease (HD) is a progressive neurodegenerative disorder where there is a pressing need for sensitive biomarkers. Aims We assessed mutant huntingtin (mHTT) and neurofilament light (NfL) in parallel. Methods CSF mHTT, CSF NfL and plasma NfL were measured using immunoassays in 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD) underwent clinical assessments, and standardized CSF and blood collections. Analysis included multiple linear regression models, Pearson’s correlations, receiver operating characteristics curves and samples sizes calculations. An event-based model was used to assess the temporal sequence of HD-related biomarker alterations. Results CSF mHTT, CSF NfL and plasma NfL were significantly higher as disease progressed and associated with all clinical measures. Both CSF and plasma NfL were associated with brain volume measures, but CSF mHTT was not. CSF mHTT, CSF NfL and plasma NfL were closely correlated, and highly stable within individuals. CSF mHTT had perfect accuracy for distinguishing between controls and HD mutation carriers, and both CSF and plasma NfL had excellent accuracy for distinguishing between premanifest and manifest HD. Sample size calculations suggest low participant numbers needed to incorporate these measures into clinical trials. The biofluid biomarkers emerged as the earliest detectable alterations in HD, followed by brain volume, motor and cognitive measures. Conclusion In this cross-sectional study we provide evidence to support mHTT and NfL as having favourable properties as biofluid biomarkers for HD. Our data suggests that these key biofluid biomarkers are some of the earliest detectable changes in HD.
Journal of Neurochemistry, May 5, 2021
Converging lines of evidence from several models, and post-mortem human brain tissue studies, sup... more 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.
Movement Disorders Clinical Practice, Nov 28, 2019
Background: Investigating early white matter (WM) change in Huntington's disease (HD) can improve... more Background: Investigating early white matter (WM) change in Huntington's disease (HD) can improve our understanding of the way in which disease spreads from the striatum. Objectives Objectives: We provide a detailed characterization of pathology-related WM change in HD. We first examined WM microstructure using diffusion-weighted imaging and then investigated both underlying biological properties of WM and products of WM damage including iron, myelin plus neurofilament light, a biofluid marker of axonal degeneration-in parallel with the mutant huntingtin protein. Methods Methods: We examined WM change in HD gene carriers from the HD-CSFcohort, baseline visit. We used standard-diffusion magnetic resonance imaging to measure metrics including fractional anisotropy, a marker of WM integrity, and diffusivity; a novel diffusion model (neurite orientation dispersion and density imaging) to measure axonal density and organization; T1-weighted and T2-weighted structural magnetic resonance imaging images to derive proxy iron content and myelin-contrast measures; and biofluid concentrations of neurofilament light (in cerebrospinal fluid (CSF) and plasma) and mutant huntingtin protein (in CSF). Results: HD gene carriers displayed reduced fractional anisotropy and increased diffusivity when compared with controls, both of which were also associated with disease progression, CSF, and mutant huntingtin protein levels. HD gene carriers also displayed proxy measures of reduced myelin contrast and iron in the striatum. Collectively, these findings present a more complete characterization of HD-related microstructural brain changes. The correlation between reduced fractional anisotropy, increased axonal orientation, and biofluid markers suggest that axonal breakdown is associated with increased WM degeneration, whereas higher quantitative T2 signal and lower myelin-contrast may indicate a process of demyelination limited to the striatum. The ongoing development of novel therapeutics to treat Huntington's disease (HD) necessitates improved characterization of HD-related brain changes. HD is a progressive neurodegenerative disorder characterized by a motor, cognitive, and neuropsychiatric phenotype and caused by CAG expansions in the huntingtin gene (HTT). Given the certainty of onset in those that inherit the gene combined with genetic testing, we can examine brain changes from the earliest, presymptomatic disease stages. Magnetic resonance imaging (MRI) measures of neuronal atrophy have characterized macrostructural brain changes associated with HD progression. Neurodegeneration primarily originates in the striatum, extending to white matter (WM) and finally the cortex. 1,3 However, although a robust marker of disease progression, macrostructural changes provide limited descriptions of pathological mechanisms underlying HD. Investigating early WM microstructural changes in HD can improve our understanding of WM organization
F: Clinical studies: case reports, observational studies and trials, 2021
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Papers by Rachael Scahill