The latest list of publications from the NIHR Cambridge Biomedical Research Centre with a brief summary. 

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Publication: Neurology

Beatrice Costa, Claudia Manzoni, Manuel Bernal-Quiros, Demis A Kia, Miquel Aguilar, Ignacio Alvarez, Victoria Alvarez, Ole Andreassen, Maria Anfossi, Silvia Bagnoli, Luisa Benussi, Livia Bernardi, Giuliano Binetti, Daniel Blackburn, Mercè Boada, Barbara Borroni, Lucy Bowns, Geir Bråthen, Amalia C Bruni, Huei-Hsin Chiang, James B Rowe et al

17 September 2020

The researchers sought to characterise C9orf72 expansions in relation to genetic ancestry and age at onset (AAO), and to use these parameters to discriminate the behavioural from the language variant syndrome, in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.

They found C9orf72 pathogenic expansions in 4% of all cases (56/1396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MNDs (11.9%), 40/800 bvFTDs (5%) and 4/495 of PPAs (0.8%). While addressing population-substructure through principal component analysis (PCA), we defined 2 patients groups with Central/Northern (n=873) and Southern European (n=523) ancestry. The proportion of expansion carriers was significantly higher in bvFTDs compared to PPAs (5% vs. 0.8% [p=2.17×10-5; OR=6.4; CI:2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs. 1.8% [p=1.1×10-2; OR=2.5; CI:1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Their prediction model (based on expansions status, genetic ancestry and AAO) predicted a diagnosis of bvFTD with 64% accuracy.

The results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry and a diagnosis of bvFTD, implying to complex genetic risk-architectures differently underpinning the behavioural and language variant syndromes.

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Publication: Journal of Neurology, Neurosurgery and Psychiatry

Tamara Paulo Tavares, Derek G V Mitchell, Kristy KL Coleman, Brenda L Coleman, Christen L Shoesmith, Christopher R Butler, Isabel Santana, Adrian Danek, Alexander Gerhard, Alexandre de Mendonca, Barbara Borroni, Maria Carmela Tartaglia, Caroline Graff, Daniela Galimberti, Fabrizio Tagliavini, Fermin Moreno, Giovanni Frisoni, James Benedict Rowe, Johannes Levin, John Cornelis Van Swieten, Markus Otto, Matthis Synofzik, Raquel Sanchez-Valle, Rik Vandenbergh, Robert Jr Laforce, Roberta Ghidoni, Sandro Sorbi, Simon Ducharme, Mario Masellis, Jonathan Rohrer, Elizabeth Finger

7 August 2020

The clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD.

The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers

The most frequently endorsed initial symptoms among symptomatic patients were apathy (23%), disinhibition (18%), memory impairments (12%), decreased fluency (8%) and impaired articulation (5%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical MAPT carriers endorsed worse mood and sleep symptoms, and C9orf72 carriers endorsed marginally greater abnormal behaviours. Preclinical GRN carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills.

Preclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group.

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Publication: NeuroImage

Catarina Rua, William T. Clark, Ian D. Driver, Olivier Mougin, Andrew T. Morgan, Stuart Clare, Susan Francis, Keith W. Muir, Richard G. Wise, T. Adrian Carpenter, Guy B. Williams, James B. Rowe, Richard Bowtell, Christopher T.Rodgers

9 September 2020

The researchers present the reliability of ultra-high field T2* MRI at 7T, as part of the UK7T Network’s “Travelling Heads” study. T2*-weighted MRI images can be processed to produce quantitative susceptibility maps (QSM) and R2* maps. These reflect iron and myelin concentrations, which are altered in many pathophysiological processes. The relaxation parameters of human brain tissue are such that R2* mapping and QSM show particularly strong gains in contrast-to-noise ratio at ultra-high field (7T) vs clinical field strengths (1.5–3T). The study team aimed to determine the inter-subject and inter-site reproducibility of QSM and R2* mapping at 7T, in readiness for future multi-site clinical studies.

Mean susceptibility (χ) and R2* values agreed broadly with literature values in all ROIs. The inter-site within-subject standard deviation was 0.001–0.005 ppm (χ) and 0.0005–0.001 ms−1 (R2*). For χ this is 2.1–4.8 fold better than 3T reports, and 1.1–3.4 fold better for R2*. The median ICC from within- and cross-site R2* data was 0.98 and 0.91, respectively. Multi-echo QSM had greater variability vs single-echo QSM especially in areas with large B0 inhomogeneity such as the inferior frontal cortex. Across sites, R2* values were more consistent than QSM in subcortical structures due to differences in B0-shimming. On a between-subject level, theirr measured χ and R2* cross-site variance is comparable to within-site variance in the literature, suggesting that it is reasonable to pool data across sites using our harmonised protocol.

The harmonized UK7T protocol and pipeline delivers on average a 3-fold improvement in the coefficient of reproducibility for QSM and R2* at 7T compared to previous reports of multi-site reproducibility at 3T. These protocols are ready for use in multi-site clinical studies at 7T.

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Publication: Brain A Journal of Neurology

Matthew J Betts, Evgeniya Kirilina, Maria C G Otaduy, Dimo Ivanov, Julio Acosta-Cabronero, Martina F Callaghan, Christian Lambert, Arturo Cardenas-Blanco, Kerrin Pine, Luca Passamonti, Clare Loane, Max C Keuken, Paula Trujillo, Falk Lüsebrink, Hendrik Mattern, Kathy Y Liu, Nikos Priovoulos, Klaus Fliessbach, Martin J Dahl, Anne Maaß, Christopher F Madelung, David Meder, Alexander J Ehrenberg, Oliver Speck, Nikolaus Weiskopf, Raymond Dolan, Ben Inglis, Duygu Tosun, Markus Morawski, Fabio A Zucca, Hartwig R Siebner, Mara Mather, Kamil Uludag, Helmut Heinsen, Benedikt A Poser, Robert Howard, Luigi Zecca, James B Rowe, Lea T Grinberg, Heidi I L Jacobs, Emrah Düzel, Dorothea Hämmerer

1 September 2020

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression.

In this article, the researchers present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases.

They outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.

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Publication: Clinical Neuropathology

Melanie P Jensen, Olivera Spasic-Boskovic, James B Rowe, Clare Galton, Kieren S J Allinson

1 September 2020

The researchers presented the clinicopathological findings of a case of combined Fahr’s disease (FD) and dementia with Lewy bodies (DLB), associated with a novel pathogenic mutation. The patient presented with visual hallucinations, fluctuating confusion and parkinsonism, leading to a presumptive diagnosis of DLB. CT scan showed extensive bilateral parenchymal calcifications, suggestive of FD. DNA sequencing identified a novel missense variant (c.92A>T p.(Asn31Ile)) in the SLC20A2 gene, a gene known to be associated with FD. This change has not been previously recorded in genetic repositories, and in silico analyses classified it as likely to be disease-causing.

Neuropathological examination revealed, macroscopically and microscopically, extensive calcification in the striatum, globus and cerebellar white matter. There was also neuronal loss in the substantia nigra and residual neurones contained alpha-synuclein-positive Lewy bodies. The neuropathology was therefore consistent with DLB and FD.

A literature review identified 3 other cases of co-existing Fahr’s and Lewy body pathology, thus the frequency of dual pathology (44%) is higher than expected by random association. Further studies are needed to determine whether alpha-synucleinopathy is linked mechanistically to FD and/or represents a phenotypic subtype.

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Publication: Journal of Alzheimer's Disease

Nicolasa Nicastro, Maura Malpetti, Thomas Cope, William Richard Bevan-Jones, Elijah Mak, Luca Passamonti, James B. Rowe, John T. O’Brien

30 June 2020

The changes of cortical structure in Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are usually described in terms of atrophy. However, neurodegenerative diseases may also affect the complexity of cortical shape, such as the fractal dimension of the brain surface.

In this study, the researchers assessed the regional patterns of cortical thickness and fractal dimension changes in a cross-sectional cohort of patients with AD and FTD.

In addition to the well-established pattern of cortical thinning encompassing temporoparietal regions in AD and frontotemporal areas in FTD, they observed reductions of fractal dimension encompassing cingulate areas and insula for both conditions, but specifically involving orbitofrontal cortex and paracentral gyrus for FTD (FDR p < 0.05). Correlational analyses between fractal dimension and cognition showed that these regions were particularly vulnerable with regards to memory and language impairment, especially in FTD.

While the present study demonstrates globally similar patterns of fractal dimension changes in AD and FTD, the researchers observed distinct cortical complexity correlates of cognitive domains impairment. Further studies are required to assess cortical complexity measures at earlier disease stages (e.g., in prodromal/asymptomatic carriers of FTD-related gene mutations) and determine whether fractal dimension represents a sensitive imaging marker for prevention and diagnostic strategies.

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Publication: Brain A Journal of Neurology

Alexander G Murley, Ian Coyle-Gilchrist, Matthew A Rouse, P Simon Jones, Win Li, Julie Wiggins, Claire Lansdall, Patricia Vázquez Rodríguez, Alicia Wilcox, Kamen A Tsvetanov, Karalyn Patterson, Matthew A Lambon Ralph, James B Rowe

1 May 2020

The syndromes caused by frontotemporal lobar degeneration have highly heterogeneous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the past decade, but the researchers propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, they examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia, non-fluent, and semantic variants of primary progressive aphasia (PPA), progressive supranuclear palsy and corticobasal syndrome. They included patients with logopenic PPA and those who met criteria for PPA but not a specific subtype.

The results show that syndromes associated with frontotemporal lobar degeneration do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders while deficits in behaviour, movement and language domains are not confined to specific diagnostic groups.

It is important to recognize individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. The researchers suggest that a transdiagnostic approach to the spectrum of frontotemporal lobar degeneration syndromes provides a useful framework with which to understand disease aetiology, progression, and heterogeneity and to target future treatments to a higher proportion of patients.

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Publication: Brain Communications

Marta M Correia, Timothy Rittman, Christopher L Barnes, Ian T Coyle-Gilchrist, Boyd Ghosh, Laura E Hughes, James B Rowe

27 April 2020

The early and accurate differential diagnosis of parkinsonian disorders is still a significant challenge for clinicians. In recent years, a number of studies have used magnetic resonance imaging data combined with machine learning and statistical classifiers to successfully differentiate between different forms of Parkinsonism. However, several questions and methodological issues remain, to minimize bias and artefact-driven classification. In this study, the researchers compared different approaches for feature selection, as well as different magnetic resonance imaging modalities, with well-matched patient groups and tightly controlling for data quality issues related to patient motion.

Their cross-validation results suggest that using principal components analysis for feature extraction provides higher classification accuracies when compared to a region-of-interest based approach. However, the differences between the two feature extraction methods were significantly reduced when an independent sample was used for validation, suggesting that the principal components analysis approach may be more vulnerable to overfitting with cross-validation. Both T1-weighted and diffusion magnetic resonance imaging data could be used to successfully differentiate between subject groups, with neither modality outperforming the other across all pairwise comparisons in the cross-validation analysis. However, features obtained from diffusion magnetic resonance imaging data resulted in significantly higher classification accuracies when an independent validation cohort was used.

Overall, the results support the use of statistical classification approaches for differential diagnosis of parkinsonian disorders. However, classification accuracy can be affected by group size, age, sex and movement artefacts. With appropriate controls and out-of-sample cross validation, diagnostic biomarker evaluation including magnetic resonance imaging based classifiers may be an important adjunct to clinical evaluation.

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Publication: Nature Genetics

Praveen Surendran, Joanna M. M. Howson et al

23 November 2020

Increased blood pressure (BP) is a major risk factor for cardiovascular disease (CVD) and related disability worldwide. Identifying biological pathways associated with blood pressure is important to understand the aetiology of CVD.

In this study involving collaborators from across the globe, and participants from diverse ancestries, researchers investigated whether genetic variants that a small proportion of people carry have an impact on blood pressure regulation and more readily implicate the genes underlying blood pressure regulation.

They identified 87 such genetic variants influencing blood pressure regulation that only a small proportion of people carry. In addition to identifying novel candidate genes associated with blood pressure, they showed a potential link between foetal development and an inverse relationship between systolic and diastolic blood pressure with stroke.

As shown in this study, a complex outcome like blood pressure requires large sample sizes to detect genetic variation associated with blood pressure that are rare in humans; studies to date have mainly looked at genetic variants that are carried by many people and therefore have very small effects on blood pressure regulation.

This study contributes to a significant improvement in researchers’ understanding of key genes controlling a risk factor like BP so they can better understand complex diseases like CVD and help identify new blood pressure therapies.

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Publication: Neurobiology of Aging

Timothy Rittman, Robin Borchert, Simon Jones, John van Swieten, Barbara Borroni, Daniela Galimberti, Mario Masellis, Maria Carmela Tartaglia, Caroline Graffi, Fabrizio Tagliavini, Giovanni B. Frisoni, Robert Laforce Jr., Elizabeth Finger, Alexandre Mendonça, Sandro Sorbi, Jonathan D. Rohrer, James B.Rowe

1 May 2019

The presymptomatic phase of neurodegenerative diseases are characterized by structural brain changes without significant clinical features. Here the researchers set out to investigate the contribution of functional network resilience to preserved cognition in presymptomatic genetic frontotemporal dementia.

They found that despite loss of both brain volume and functional connections, there is maintenance of an efficient topological organization of the brain’s functional network in the years leading up to the estimated age of frontotemporal dementia symptom onset. After this point, functional network efficiency declines markedly. Reduction in connectedness was most marked in highly connected hub regions.

Measures of topological efficiency of the brain’s functional network and organization predicted cognitive dysfunction in domains related to symptomatic frontotemporal dementia and connectivity correlated with brain volume loss in frontotemporal dementia. The researchers propose that maintaining the efficient organization of the brain’s functional network supports cognitive health even as atrophy and connectivity decline presymptomatically.

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Publication: Annals of Clinical and Translational Neurology

W. Richard Bevan-Jones, Thomas E. Cope, P. Simon Jones, Luca Passamonti, Young T. Hong, Tim Fryer, Robert Arnold, Jonathan P. Coles, Franklin I. Aigbirhio, John T. O’Brien, James B. Rowe

1 March 2019

Neuroinflammation occurs in frontotemporal dementia, however its timing relative to protein aggregation and neuronal loss is unknown.

Using positron emission tomography and magnetic resonance imaging to quantify these processes in a pre‐symptomatic carrier of the 10 + 16 MAPT mutation, the researchers show microglial activation in frontotemporal regions, despite a lack of protein aggregation or atrophy in these areas.

The distribution of microglial activation better discriminated the carrier from controls than did protein aggregation at this pre‐symptomatic disease stage. The findings suggest an early role for microglial activation in frontotemporal dementia. Longitudinal studies are needed to explore the causality of this pathophysiological association.

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Publication: Neurobiology of Aging

Ece Kocagoncu, Andrew Quinn, Azadeh Firouzian, Elisa Cooper, Andrea Greve, Roger Gunn, Gary Green, Mark W. Woolrich, Richard N.Henson, Simon Lovestone, James B.Rowe

1 August 2020

Understanding the role of Tau protein aggregation in the pathogenesis of Alzheimer’s disease is critical for the development of new Tau-based therapeutic strategies to slow or prevent dementia. The researchers tested the hypothesis that Tau pathology is associated with functional organization of widespread neurophysiological networks.

They found that higher Tau burden in early Alzheimer’s disease was associated with a shift away from the optimal small-world organization and a more fragmented network in the beta and gamma bands, whereby parieto-occipital areas were disconnected from the anterior parts of the network.

The results support the translational development of neurophysiological “signatures” of Alzheimer’s disease, to understand disease mechanisms in humans and facilitate experimental medicine studies.

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