Publications

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

If you are publishing research which has had funding and / or support from the NIHR Cambridge Biomedical Research Centre, please complete this form

View publication

Publication: Annals of Neurology

Maura Malpetti, Luca Passamonti, Timothy Rittman, P. Simon Jones, Patricia Vázquez Rodríguez, W. Richard Bevan‐Jones, Young T. Hong, Tim D. Fryer, Franklin I. Aigbirhio, John T. O’Brien, James B. Rowe

20 September 2020


The researchers examined the relationship between tau pathology and neuroinflammation using [11C]PK11195 and [18F]AV‐1451 PET in 17 patients with progressive supranuclear palsy (PSP) Richardson’s syndrome. They tested the hypothesis that neuroinflammation and tau protein aggregation colocalize macroscopically, and correlate with clinical severity.

Regional [11C]PK11195 and [18F]AV‐1451 binding were positively correlated (R = 0.577, p < 0.0001). The PCA identified 4 components for each ligand, reflecting the relative expression of tau pathology or neuroinflammation in distinct groups of brain regions. Positive associations between [11C]PK11195 and [18F]AV‐1451 components’ loadings were found in both subcortical (R = 0.769, p < 0.0001) and cortical regions (R = 0.836, p < 0.0001). There were positive correlations between clinical severity and both subcortical tau pathology (R = 0.667, p = 0.003) and neuroinflammation (R = 0.788, p < 0.001).

The researchers show that tau pathology and neuroinflammation colocalize in PSP, and that individual differences in subcortical tau pathology and neuroinflammation are linked to clinical severity. Although longitudinal studies are needed to determine causal associations between these molecular pathologies, they suggest that the combination of tau‐ and immune‐oriented strategies may be useful for effective disease‐modifying treatments in PSP

View publication

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.

View publication

Publication: Neuropsychopharmacology

Rafa Romero-Garcia, Roxanne W. Hook, Jeggan Tiego, Richard A. I. Bethlehem, Ian M. Goodyer, Peter B. Jones, Ray Dolan, Jon E. Grant, Edward T. Bullmore, Murat Yücel & Samuel R. Chamberlain

12 September 2020


Summary

Impulsivity refers to behaviours that are inappropriate, risky, unduly hasty, and that lead to untoward outcomes. By contrast, compulsivity refers to repetitive, perseverative actions that are excessive and inappropriate to a given situation.

For example, an individual with attention-deficit hyperactivity disorder (ADHD) may manifest impulsive problems such as making a statement they regret to a colleague; or jumping a red light; whereas an individual with obsessive-compulsive disorder (OCD) may repeatedly (i.e. compulsively) check the front door is locked, for hours per occasion.

It is well known that impulsive and compulsive problems often occur together in the same individual, but very little is known about processes in the brain that may contribute to this. To address this, in this study supported by the NIHR Cambridge BRC researchers studied brain structure and impulsive-compulsive problems in young adults, and the relationship between them.

They found that most of the occurrence of impulsive and compulsive problems could be explained by difficulty regulating urges and habits, known as ‘disinhibition’. Disinhibition was related to changes in the structure of the brain, especially in regions important for top-down control such as the frontal lobe.

The study identified a new brain-based vulnerability marker contributing to impulsive and compulsive problems. Unlike previous research, the findings go beyond traditional psychiatric diagnostic boundaries, by examining a comprehensive range of behaviors, rather than only one disorder studied in isolation.

View publication

Publication: Journal of Neurology, Neurosurgery and Psychiatry

Audrey Low, Elijah Mak, Maura Malpetti, Luca Passamonti, Nicolas Nicastro, James D Stefaniak, George Savulich, Leonidas Chouliaras, Li Su, James B Rowe, Hugh S Markus, John T O’Brien

11 September 2020


Associations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. In this study researchers investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [11C]PK11195 positron emission tomography (PET) imaging.

Global [11C]PK11195 binding was associated with SVD markers, particularly in regions typical of hypertensive arteriopathy: deep microbleeds (β=0.63, F(1,35)=35.24, p<0.001), deep WMH (β=0.59, t=4.91, p<0.001). In dominance analysis, hypertensive arteriopathy score outperformed CAA in predicting [11C]PK11195 binding globally and in 28 out of 37 regions of interest, especially the medial temporal lobe (β=0.66–0.76, t=3.90–5.58, FDR-corrected p (pFDR)=<0.001–0.002) and orbitofrontal cortex (β=0.51–0.57, t=3.53–4.30, pFDR=0.001–0.004).

Microglial activation is associated with SVD, particularly with the hypertensive arteriopathy subtype of SVD. Although further research is needed to determine causality, this study suggests that targeting neuroinflammation might represent a novel therapeutic strategy for SVD.

View publication

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.

View publication

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.

View publication

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.

View publication

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.

View publication

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.

View publication

Publication: Movement Disorders

Negin Holland, P. Simon Jones, George Savulich, Julie K. Wiggins, Young T. Hong, Tim D. Fryer, Roido Manavaki, Selena Milicevic Sephton, Istvan Boros, Maura Malpetti, Frank H. Hezemans, Franklin I. Aigbirhio, Jonathan P. Coles, John O’Brien, James B. Rowe

11 July 2020


In this study the researchers tested the hypothesis that synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) (Richardson’s syndrome) and amyloid‐negative corticobasal syndrome (CBS).

Nine CBS patients had negative amyloid biomarkers determined by [11C]PiB PET and hence were deemed likely to have corticobasal degeneration (CBD). Patients with PSP‐Richardson’s syndrome and amyloid‐negative CBS were impaired in executive, memory, and visuospatial tasks. [11C]UCB‐J binding was reduced across frontal, temporal, parietal, and occipital lobes, cingulate, hippocampus, insula, amygdala, and subcortical structures in both PSP and CBD patients compared to controls (P < 0.01), with median reductions up to 50%, consistent with postmortem data. Reductions of 20% to 30% were widespread even in areas of the brain with minimal atrophy. There was a negative correlation between global [11C]UCB‐J binding and the PSP and CBD rating scales (R = –0.61, P < 0.002; R = –0.72, P < 0.001, respectively) and a positive correlation with the revised Addenbrooke’s Cognitive Examination (R = 0.52; P = 0.01).

The researchers confirm severe synaptic loss in PSP and CBD in proportion to disease severity, providing critical insight into the pathophysiology of primary degenerative tauopathies. [11C]UCB‐J may facilitate treatment strategies for disease‐modification, synaptic maintenance, or restoration.

View publication

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.

View publication

Publication: Neurobiology of Aging

Nicolas Nicastro, Maura Malpetti, Elijah Mak, Guy B. Williams, W. Richard Bevan-Jones, Stephen F. Carter, Luca Passamonti, Tim D. Fryer, Young T. Hong, Franklin I. Aigbirhiod, James B. Rowe, John T. O’Brien

17 June 2020


Neuroinflammation is increasingly recognized as playing a key pathogenetic role in Alzheimer’s disease (AD). Here the researchers examined the relationship between in vivo neuroinflammation and gray matter (GM) changes.

AD/mild cognitive impairment participants exhibited GM atrophy and cortical thinning in AD-related temporoparietal regions (false discovery rate–corrected p < 0.05). Patients also showed increased microglial activation in temporal cortices. Higher 11C-PK11195 binding in these regions was associated with reduced volume and cortical thickness in parietal, occipital, and cingulate areas (false discovery rate p < 0.05). Hippocampal GM atrophy and parahippocampal cortical thinning were related to worse cognition (p < 0.05), but these effects were not mediated by microglial activation.

This study demonstrates an association between in vivo microglial activation and markers of GM damage in AD, positioning neuroinflammation as a potential target for immunotherapeutic strategies.

View publication
Discover more

If you would like more information about NIHR Cambridge BRC, please contact us.

Events Calendar

Listing relevant events and training sessions for researchers and members of the public.