Publications by authors named "Alexander J Lowe"

8 Publications

  • Page 1 of 1

Kynurenine pathway metabolites in cerebrospinal fluid and blood as potential biomarkers in Huntington's disease.

J Neurochem 2021 Apr 2. Epub 2021 Apr 2.

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.

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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http://dx.doi.org/10.1111/jnc.15360DOI Listing
April 2021

Cerebrospinal fluid endo-lysosomal proteins as potential biomarkers for Huntington's disease.

PLoS One 2020 17;15(8):e0233820. Epub 2020 Aug 17.

UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.

Molecular markers derived from cerebrospinal fluid (CSF) represent an accessible means of exploring the pathobiology of Huntington's disease (HD) in vivo. The endo-lysosomal/autophagy system is dysfunctional in HD, potentially contributing to disease pathogenesis and representing a potential target for therapeutic intervention. Several endo-lysosomal proteins have shown promise as biomarkers in other neurodegenerative diseases; however, they have yet to be fully explored in HD. We performed parallel reaction monitoring mass spectrometry analysis (PRM-MS) of multiple endo-lysosomal proteins in the CSF of 60 HD mutation carriers and 20 healthy controls. Using generalised linear models controlling for age and CAG, none of the 18 proteins measured displayed significant differences in concentration between HD patients and controls. This was affirmed by principal component analysis, in which no significant difference across disease stage was found in any of the three components representing lysosomal hydrolases, binding/transfer proteins and innate immune system/peripheral proteins. However, several proteins were associated with measures of disease severity and cognition: most notably amyloid precursor protein, which displayed strong correlations with composite Unified Huntington's Disease Rating Scale, UHDRS Total Functional Capacity, UHDRS Total Motor Score, Symbol Digit Modalities Test and Stroop Word Reading. We conclude that although endo-lysosomal proteins are unlikely to have value as disease state CSF biomarkers for Huntington's disease, several proteins demonstrate associations with clinical severity, thus warranting further, targeted exploration and validation in larger, longitudinal samples.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233820PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430717PMC
October 2020

Motor hyperactivation during cognitive tasks: An endophenotype of juvenile myoclonic epilepsy.

Epilepsia 2020 07 25;61(7):1438-1452. Epub 2020 Jun 25.

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.

Objective: Juvenile myoclonic epilepsy (JME) is the most common genetic generalized epilepsy syndrome. Myoclonus may relate to motor system hyperexcitability and can be provoked by cognitive activities. To aid genetic mapping in complex neuropsychiatric disorders, recent research has utilized imaging intermediate phenotypes (endophenotypes). Here, we aimed to (a) characterize activation profiles of the motor system during different cognitive tasks in patients with JME and their unaffected siblings, and (b) validate those as endophenotypes of JME.

Methods: This prospective cross-sectional investigation included 32 patients with JME, 12 unaffected siblings, and 26 controls, comparable for age, sex, handedness, language laterality, neuropsychological performance, and anxiety and depression scores. We investigated patterns of motor system activation during episodic memory encoding and verb generation functional magnetic resonance imaging (fMRI) tasks.

Results: During both tasks, patients and unaffected siblings showed increased activation of motor system areas compared to controls. Effects were more prominent during memory encoding, which entailed hand motion via joystick responses. Subgroup analyses identified stronger activation of the motor cortex in JME patients with ongoing seizures compared to seizure-free patients. Receiver-operating characteristic curves, based on measures of motor activation, accurately discriminated both patients with JME and their siblings from healthy controls (area under the curve: 0.75 and 0.77, for JME and a combined patient-sibling group against controls, respectively; P < .005).

Significance: Motor system hyperactivation represents a cognitive, domain-independent endophenotype of JME. We propose measures of motor system activation as quantitative traits for future genetic imaging studies in this syndrome.
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http://dx.doi.org/10.1111/epi.16575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681252PMC
July 2020

Myeloarchitecture gradients in the human insula: Histological underpinnings and association to intrinsic functional connectivity.

Neuroimage 2020 08 20;216:116859. Epub 2020 Apr 20.

Multimodal Imaging and Connectome Analysis Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada. Electronic address:

Insular cortex is a core hub involved in multiple cognitive and socio-affective processes. Yet, the anatomical mechanisms that explain how it is involved in such a diverse array of functions remain incompletely understood. Here, we tested the hypothesis that changes in myeloarchitecture across the insular cortex explain how it can be involved in many different facets of cognitive function. Detailed intracortical profiling, performed across hundreds of insular locations on the basis of myelin-sensitive magnetic resonance imaging (MRI), was compressed into a lower-dimensional space uncovering principal axes of myeloarchitectonic variation. Leveraging two datasets with different high-resolution MRI contrasts, we obtained robust support for two principal dimensions of insular myeloarchitectonic differentiation in vivo, one running from ventral anterior to posterior banks and one radiating from dorsal anterior towards both ventral anterior and posterior subregions. Analyses of post mortem 3D histological data showed that the antero-posterior axis was mirrored in cytoarchitectural markers, even when controlling for sulco-gyral folding. Resting-state functional connectomics in the same individuals and ad hoc meta-analyses showed that myelin gradients in the insula relate to diverse affiliation to macroscale intrinsic functional systems, showing differential shifts in functional network embedding across each myelin-derived gradient. Collectively, our findings offer a novel approach to capture structure-function interactions of a key node of the limbic system, and suggest a multidimensional structural basis underlying the diverse functional roles of the insula.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116859DOI Listing
August 2020

Targeting age-related differences in brain and cognition with multimodal imaging and connectome topography profiling.

Hum Brain Mapp 2019 12 24;40(18):5213-5230. Epub 2019 Aug 24.

Multimodal Imaging and Connectome Analysis Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.

Aging is characterized by accumulation of structural and metabolic changes in the brain. Recent studies suggest transmodal brain networks are especially sensitive to aging, which, we hypothesize, may be due to their apical position in the cortical hierarchy. Studying an open-access healthy cohort (n = 102, age range = 30-89 years) with MRI and Aβ PET data, we estimated age-related cortical thinning, hippocampal atrophy and Aβ deposition. In addition to carrying out surface-based morphological and metabolic mapping experiments, we stratified effects along neocortical and hippocampal resting-state functional connectome gradients derived from independent datasets. The cortical gradient depicts an axis of functional differentiation from sensory-motor regions to transmodal regions, whereas the hippocampal gradient recapitulates its long-axis. While age-related thinning and increased Aβ deposition occurred across the entire cortical topography, increased Aβ deposition was especially pronounced toward higher-order transmodal regions. Age-related atrophy was greater toward the posterior end of the hippocampal long-axis. No significant effect of age on Aβ deposition in the hippocampus was observed. Imaging markers correlated with behavioral measures of fluid intelligence and episodic memory in a topography-specific manner, confirmed using both univariate as well as multivariate analyses. Our results strengthen existing evidence of structural and metabolic change in the aging brain and support the use of connectivity gradients as a compact framework to analyze and conceptualize brain-based biomarkers of aging.
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http://dx.doi.org/10.1002/hbm.24767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864903PMC
December 2019

Multiscale Structure-Function Gradients in the Neonatal Connectome.

Cereb Cortex 2020 01;30(1):47-58

Multimodal Imaging and Connectome Analysis Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.

The adult functional connectome is well characterized by a macroscale spatial gradient of connectivity traversing from unimodal toward higher-order transmodal cortices that recapitulates known principles of hierarchical organization and myelination patterns. Despite an emerging literature assessing connectome properties in neonates, the presence of connectome gradients and particularly their correspondence to microstructure remains largely unknown. We derived connectome gradients using unsupervised techniques applied to functional connectivity data from 40 term-born neonates. A series of cortex-wide analysis examined associations to magnetic resonance imaging-derived morphological parameters (cortical thickness, sulcal depth, curvature), measures of tissue microstructure (intracortical T1w/T2w intensity, superficial white matter diffusion parameters), and subcortico-cortical functional connectivity. Our findings indicate that the primary neonatal connectome gradient runs between sensorimotor and visual anchors and captures specific associations to cortical and superficial white matter microstructure as well as thalamo-cortical connectivity. A second gradient indicated an anterior-to-posterior asymmetry in macroscale connectivity alongside an immature differentiation between unimodal and transmodal areas, indicating a connectome-level circuitry en route to an adult-like organization. Our findings reveal an important coordination of structural and functional interactions in the neonatal connectome across spatial scales. Observed associations were replicable across individual neonates, suggesting consistency and generalizability.
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http://dx.doi.org/10.1093/cercor/bhz069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029695PMC
January 2020

Neuroimaging and connectomics of drug-resistant epilepsy at multiple scales: From focal lesions to macroscale networks.

Epilepsia 2019 04 19;60(4):593-604. Epub 2019 Mar 19.

Multimodal Imaging and Connectome Analysis Lab, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

Epilepsy is among the most common chronic neurologic disorders, with 30%-40% of patients having seizures despite antiepileptic drug treatment. The advent of brain imaging and network analyses has greatly improved the understanding of this condition. In particular, developments in magnetic resonance imaging (MRI) have provided measures for the noninvasive characterization and detection of lesions causing epilepsy. MRI techniques can probe structural and functional connectivity, and network analyses have shaped our understanding of whole-brain anomalies associated with focal epilepsies. This review considers the progress made by neuroimaging and connectomics in the study of drug-resistant epilepsies due to focal substrates, particularly temporal lobe epilepsy related to mesiotemporal sclerosis and extratemporal lobe epilepsies associated with malformations of cortical development. In these disorders, there is evidence of widespread disturbances of structural and functional connectivity that may contribute to the clinical and cognitive prognosis of individual patients. It is hoped that studying the interplay between macroscale network anomalies and lesional profiles will improve our understanding of focal epilepsies and assist treatment choices.
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http://dx.doi.org/10.1111/epi.14688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447443PMC
April 2019

Forensic utility of a nitrogen and oxygen isotope ratio time series of ammonium nitrate and its isolated ions.

Talanta 2018 Feb 5;178:94-101. Epub 2017 Sep 5.

FBI Laboratory - Counterterrorism and Forensic Science Research Unit, Quantico, VA 22135, USA.

Ammonium nitrate (AN) based fertilizers are inexpensive and easily obtained, characteristics that often lead to their use in homemade explosive devices. The stable nitrogen and oxygen isotope ratios (N/N and O/O, expressed as δN and δO) of AN have the potential to aid in forensic investigations by providing supplemental properties for sample-to-sample comparison in materials which are otherwise chemically identical. The forensic utility of stable isotope analyses depends on demonstrated variation between different sources and minimal variation within a source. To test the variability within a single manufacturer (here considered a source), a total of 26 samples representing two production time periods and two product lines were analyzed for bulk δN and δO. Additionally, because AN is known to have a modest isotopic range, a potassium nitrate precipitation method was developed to separate the component ions (NO and NH) for individual δN analysis and increased discriminatory power. The average δN and δO of bulk AN (- 0.10‰ and + 22.8‰, respectively) is similar to the isotopic signature of atmospheric N and O, the starting reactants in AN production. The bulk δN, δO, and NO δN show average values from both product lines that differ by 1.5‰, 2.0‰, and 2.6‰, respectively, between the production periods of June and November 2015. Conversely, the NH δN remained relatively consistent over time. Furthermore, whereas samples in the two product lines produced on the same day in June are isotopically similar, there are isotopic differences between samples in the two product lines manufactured within 6h of each other in November. The observed variability could be useful in comparing AN from two or more bombs, or a bomb and a stash of AN in a suspect's possession, but the observed lot-to-lot differences within one manufacturer could complicate attribution efforts. In contrast, the NH δN values, which appear to be the most consistent over time within this factory, need to be further explored as a potentially reliable signal.
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http://dx.doi.org/10.1016/j.talanta.2017.08.105DOI Listing
February 2018