Publication: Current Biology

Amilla L. Nord, Edwin S. Dalmaijer, Thomas Armstrong, Kate Baker, Tim Dalgleish

24 November 2020

Summary:

Disgust is a natural response to unpleasant sights, but for some people, disgust can become pathological, affecting their mental health and quality of life.

Researchers have shown that domperidone, a commonly-prescribed anti-nausea medicine, can help significantly reduce how much volunteers look away from disgusting images. Read the full news story.

Publication: Cancers

Contributing NIHR Cambridge BRC researchers: Andrew B Gill, Leonardo Rundo, Jonathan C. M. Wan, Doreen Lau, Jeries P. Zawaideh, Ramona Woitek, Fulvio Zaccagna, Lucian Beer, Davina Gale, Evis Sala, Dominique-Laurent Couturier, Pippa G. Corrie, Nitzan Rosenfeld and Ferdia A. Gallagher

24 November 2020

The analysis of circulating tumor DNA (ctDNA) concentrations in blood plasma and the radiomic analysis of tumor images (i.e., quantification of textural features on medical imaging) have both been used to provide information about cancer progression. The purpose of this study was to assess a link between these two different modalities in order to determine whether results from one can be used to predict outcomes from the other.

The results show that radiomics features can predict ctDNA levels in patients with metastatic melanoma even when controlling for other factors such as tumor volume.

This establishes the potential for new biomarkers of tumor progression that could combine the specificity of ctDNA assays with the high-resolution spatial information obtained by imaging. This could enable more accurate assessment of tumor response to treatment and provide clinicians with more timely indications of whether a particular therapeutic option is working or not.

Publication: Alzheimer's and Dementia

Kamen A. Tsvetanov, Stefano Gazzina, P. Simon Jones, John van Swieten, Barbara Borroni, Raquel Sanchez‐Valle, Fermin Moreno, James B. Rowe et al

20 November 2020

The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. The research team investigate this phenomenon in familial frontotemporal dementia (FTD).

There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, the researchers identified behaviorally relevant structural and functional network differences. Structure‐function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non‐carriers, and increased with proximity to the expected onset of disease.

The findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance.

Publication: Neurobiology of Aging

Elijah Mak, Nicolas Nicastro, Maura Malpetti, George Savulich, Ajenthan Surendranathan, Negin Holland, Luca Passamonti, Simon P. Jones, Stephen F. Carter, Li Su Young T.Hong, Tim D.Fryer, Guy B. Williams, Franklin Aigbirhio, James B. Rowe & John T. O’Brien

14 November 2020

Alzheimer’s disease (AD) pathology is frequently observed as a comorbidity in people with dementia with Lewy bodies (DLB). Here, the research team evaluated the in vivo distribution of tau burden and its influence on the clinical phenotype of DLB.

Tau deposition was quantified using [18F]-AV1451 positron emission tomography in people with DLB (n = 11) and AD (n = 27), and healthy controls (n = 14). A subset of subjects with Lewy body diseases (n = 4) also underwent [11C]-PK11195 PET to estimate microglial activation. [18F]-AV1451 BPND was lower in DLB compared to AD across widespread regions. The medial temporal lobe [18F]-AV1451 BPND distinguished people with DLB from AD (AUC = 0.87), and negatively correlated with ACE-R and MMSE. There was a high degree of colocalisation between [18F]-AV1451 and [11C]-PK11195 binding (p<0.001).

The findings of minimal tau burden in DLB confirm previous studies. Nevertheless, the associations of [18F]-AV1451 binding with cognitive impairment, suggest that tau may interact synergistically with other pathological processes to aggravate disease severity in DLB.

Publication: Brain A Journal of Neurology

Alexander G Murley, Matthew A Rouse, P Simon Jones, Rong Ye, Frank H Hezemans, Claire O’Callaghan, Polytimi Frangou, Zoe Kourtzi, Catarina Rua, T Adrian Carpenter, Christopher T Rodgers, James B Rowe

3 November 2020

Behavioural disinhibition is a common feature of the syndromes associated with frontotemporal lobar degeneration (FTLD). It is associated with high morbidity and lacks proven symptomatic treatments. A potential therapeutic strategy is to correct the neurotransmitter deficits associated with FTLD, thereby improving behaviour. Reductions in the neurotransmitters glutamate and GABA correlate with impulsive behaviour in several neuropsychiatric diseases and there is post-mortem evidence of their deficit in FTLD. Here, the researchers tested the hypothesis that prefrontal glutamate and GABA levels are reduced by FTLD in vivo, and that their deficit is associated with impaired response inhibition.

They measured glutamate and GABA levels using semi-LASER magnetic resonance spectroscopy in the right inferior frontal gyrus, because of its strong association with response inhibition, and in the primary visual cortex, as a control region. The stop-signal reaction time was calculated using an ex-Gaussian Bayesian model. Participants with frontotemporal dementia and progressive supranuclear palsy had impaired response inhibition, with longer stop-signal reaction times compared with controls. GABA concentration was reduced in patients versus controls in the right inferior frontal gyrus, but not the occipital lobe. There was no group-wise difference in partial volume corrected glutamate concentration between patients and controls. Both GABA and glutamate concentrations in the inferior frontal gyrus correlated inversely with stop-signal reaction time, indicating greater impulsivity in proportion to the loss of each neurotransmitter.

The researchers conclude that the glutamatergic and GABAergic deficits in the frontal lobe are potential targets for symptomatic drug treatment of frontotemporal dementia and progressive supranuclear palsy.

Publication: Journal of Neurology, Neurosurgery & Psychiatry

Maura Malpetti, Timothy Rittman, Peter Simon Jones, Thomas Edmund Cope, Luca Passamonti, William Richard Bevan-Jones, Karalyn Patterson, Tim D Fryer, Young T Hong, Franklin I Aigbirhio, John Tiernan O’Brien, James Benedict Rowe

29 October 2020

The researchers report in vivo patterns of neuroinflammation and abnormal protein aggregation in seven cases of familial frontotemporal dementia (FTD) with mutations in MAPT, GRN and C9orf72 genes.

Patients with familial FTD across all mutation groups showed increased [11C]PK11195 binding predominantly in frontotemporal regions, with additional regions showing abnormalities in individuals. Patients with MAPT mutations had a consistent distribution of [18F]AV-1451 binding across the brain, with heterogeneous distributions among carriers of GRN and C9orf72 mutations.

This case series suggests that neuroinflammation is part of the pathophysiology of familial FTD, warranting further consideration of immunomodulatory therapies for disease modification and prevention.

Publication: Movement Disorders

Samuel Shribman, Carolin Heller, Maggie Burrows, Amanda Heslegrave,Imogen Swift, Martha S. Foiani, Godfrey T. Gillett, Emmanuel A. Tsochatzis, James B. Rowe et al

20 October 2020

Outcomes are unpredictable for neurological presentations of Wilson’s disease (WD). Dosing regimens for chelation therapy vary and monitoring depends on copper indices, which do not reflect end‐organ damage. The objective was to identify a biomarker for neurological involvement in WD.

Unlike copper indices, neurofilament light (NfL) concentrations were higher in neurological than hepatic presentations. They were also higher in those with active neurological disease when controlling for severity and correlated with neurological examination subscores in stable patients.

NfL is a biomarker of neurological involvement with potential use in guiding chelation therapy and clinical trials for novel treatments.

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

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 research shows 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, the researchers suggest that the combination of tau‐ and immune‐oriented strategies may be useful for effective disease‐modifying treatments in PSP

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.

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.

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.