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

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Publication: Journal of Neurology Neurosurgery and Psychiatry

Carolin Heller, Martha S Foiani, Katrina Moore, Rhian Convery, Martina Bocchetta, Mollie Neason, David M Cash, David Thomas, Caroline V Greaves, Ione OC Woollacott, Rachelle Shafei, John C Van Swieten, Fermin Moreno, Raquel Sanchez-Valle, Barbara Borroni, Robert Laforce Jr, Mario Masellis, Maria Carmela Tartaglia, Caroline Graff, Daniela Galimberti, James B Rowe et al

14 January 2020

There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker.

In this research, the team found out that plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers.

Raised GFAP concentrations appear to be unique to GRN-related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials.

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Publication: Neurology

Tamara P. Tavares, Derek G.V. Mitchell, Kristy Coleman, Christen Shoesmith, Robert Bartha, David M. Cash, Katrina M. Moore, John van Swieten, Barbara Borroni, Daniela Galimberti, Maria Carmela Tartaglia, James Rowe, Caroline Graff, Fabrizio Tagliavini, Giovanni Frisoni, Stefano Cappa, Robert Laforce, Alexandre de Mendonça, Sandro Sorbi, Garrick Wallstrom, Mario Masellis, Jonathan D. Rohrer, Elizabeth C. Finger

29 October 2019

The objective of this research was to characterize the time course of ventricular volume expansion in genetic frontotemporal dementia (FTD) and identify the onset time and rates of ventricular expansion in presymptomatic FTD mutation carriers. Participants included patients with a mutation in MAPT, PGRN, or C9orf72, or first-degree relatives of mutation carriers from the GENFI study with MRI scans at study baseline and at 1 year follow-up. The researchers aimed to identify identify differences in ventricular volume and in expansion rates as a function of time to expected disease onset between presymptomatic carriers and noncarriers.

Ventricular volume differences were observed 4 years prior to symptom disease onset for presymptomatic carriers compared to noncarriers. Annualized rates of ventricular volume expansion were greater in presymptomatic carriers relative to noncarriers. Importantly, time-intensive manually edited and fully automated ventricular volume resulted in similar findings.

Ventricular volume differences are detectable in presymptomatic genetic FTD. Concordance of results from time-intensive manual editing and fully automatic segmentation approaches support its value as a measure of disease onset and progression in future studies in both presymptomatic and symptomatic genetic FTD.

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Publication: Brain A Journal of Neurology

Maura Malpetti, Rogier A Kievit, Luca Passamonti, P Simon Jones, Kamen A Tsvetanov, Timothy Rittman, Elijah Mak, Nicolas Nicastro, W Richard Bevan-Jones, Li Su, Young T Hong, Tim D Fryer, Franklin I Aigbirhio, John T O’Brien, James B Rowe

7 May 2020

Tau pathology, neuroinflammation, and neurodegeneration are key aspects of Alzheimer’s disease. Understanding whether these features predict cognitive decline, alone or in combination, is crucial to develop new prognostic measures and enhanced stratification for clinical trials. Here, the researchers studied how baseline assessments of in vivo tau pathology (measured by 18F-AV-1451 PET), neuroinflammation (measured by 11C-PK11195 PET) and brain atrophy (derived from structural MRI) predicted longitudinal cognitive changes in patients with Alzheimer’s disease pathology.

In patients, both stepwise backward elimination and Bayesian model selection revealed an optimal predictive model that included both components of 18F-AV-1451 and the first (i.e. anterior temporal) component for 11C-PK11195. However, the MRI-derived atrophy component and demographic variables were excluded from the optimal predictive model of cognitive decline.

The researchers conclude that temporo-parietal tau pathology and anterior temporal neuroinflammation predict cognitive decline in patients with symptomatic Alzheimer’s disease pathology. This indicates the added value of PET biomarkers in predicting cognitive decline in Alzheimer’s disease, over and above MRI measures of brain atrophy and demographic data. The findings also support the strategy for targeting tau and neuroinflammation in disease-modifying therapy against Alzheimer’s disease.

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Publication: The Journal of Neuroscience

L. Passamonti, K.A. Tsvetanov, P.S. Jones, W.R. Bevan-Jones, R. Arnold, R.J. Borchert, E. Mak, L. Su, J.T. O’Brien and J.B. Rowe

18 July 2019

Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer’s disease. The researchers tested the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment.

Patients showed significantly higher [11C]PK11195 binding relative to controls, in a distributed spatial pattern including the hippocampus, medial, and inferior temporal cortex. Patients with enhanced loading on this [11C]PK11195 binding distribution displayed diffuse abnormal functional connectivity. The expression of a stronger association between such abnormal connectivity and higher levels of neuroinflammation correlated with worse cognitive deficits.

This study suggests that neuroinflammation relates to the pathophysiological changes in network function that underlie cognitive deficits in Alzheimer’s disease. Neuroinflammation, and its association with functionally-relevant reorganisation of brain networks, is proposed as a target for emerging immuno-therapeutic strategies aimed at preventing or slowing the emergence of dementia.

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Publication: Journal of Neurology

Julie Wiggins, Claire J. Lansdall, Kate Dawson, Timothy Rittman & James B. Rowe

2 July 2019

In this study the researchers aimed to validate the use of the Test Your Memory (TYM) test in dementias other than Alzheimer’s disease, and to compare the TYM test to two other short cognitive tests.

Patients scored an average of 34.4/50 on the TYM test compared to 46.0/50 in age-matched controls. Using the threshold of 42/50, the TYM test detected 80% of non-Alzheimer dementias. The area under the ROC curve was 0.89 with a PPV of 0.80 and a NPV of 0.84. The TYM test performed better than the ACE-R (using the threshold of 83) which detected 69% of cases and the MMSE (using a threshold of 24) which detected only 27%.

The TYM test is a useful test in the detection of non-Alzheimer dementia. The TYM test performs much better than the MMSE at detecting non-Alzheimer dementias.

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Publication: Alzheimer's and Dementia Diagnosis, Assessment & Disease Monitoring

Laura E. Hughes, Richard N. Henson, Ernesto Pereda, Ricardo Bruña, David López‐Sanz, Andrew J. Quinn, Mark W. Woolrich, Anna C. Nobre, James B. Rowe, Fernando Maestú

14 June 2019

An increasing number of studies are using magnetoencephalography (MEG) to study dementia. Here the researchers defined a common methodological framework for MEG resting‐state acquisition and analysis to facilitate the pooling of data from different sites.

They found that the spectral analyses confirmed frequency‐specific differences in patients with MCI, both in power and connectivity patterns, with highest classification accuracy from connectivity. Critically, site acquisition differences did not dominate the results.

This work provides detailed protocols and analyses that are sensitive to cognitive impairment, and that will enable standardized data sharing to facilitate large‐scale collaborative projects.

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Publication: Journal of Neurology, Neurosurgery and Psychiatry

Stefano Gazzina, Mario Grassi, Enrico Premi, Maura Cosseddu, Antonella Alberici, Silvana Archetti, Roberto Gasparotti, John Van Swieten, Daniela Galimberti, Raquel Sanchez-Valle, Robert Jr Laforce, Fermin Moreno, Matthis Synofzik, Caroline Graff, Mario Masellis, Maria Carmela Tartaglia, James B Rowe, Rik Vandenberghe, Elizabeth Finger, Fabrizio Tagliavini, Alexandre de Mendonça, Isabel Santana, Christopher R Butler, Simon Ducharme, Alex Gerhard, Adrian Danek, Johannes Levin, Markus Otto, Giovanni Frisoni, Sandro Sorbi, Alessandro Padovani, Jonathan D Rohrer, Barbara Borroni

10 June 2019

Cognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, the researchers examined the effect of education on grey matter loss over time.

Highly educated at-risk subjects had better cognition and higher grey matter volume at baseline; moreover, higher educational attainment was associated with slower loss of grey matter over time in mutation carriers.

This longitudinal study demonstrates that even in presence of ongoing pathological processes, education may facilitate both brain reserve and brain maintenance in the presymptomatic phase of genetic FTD.

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Publication: Cerebral Cortex

19 June 2019

The analysis of neural circuits can provide crucial insights into the mechanisms of neurodegeneration and dementias, and offer potential quantitative biological tools to assess novel therapeutics. Here the researchers used behavioral variant frontotemporal dementia (bvFTD) as a model disease.

They demonstrated that inversion of canonical microcircuit models to noninvasive human magnetoencephalography, using dynamic causal modeling, can identify the regional- and laminar-specificity of bvFTD pathophysiology, and their parameters can accurately differentiate patients from matched healthy controls.

The research team suggests that this approach provides an in vivo platform for testing mechanistic hypotheses about disease progression and pharmacotherapeutics.

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Publication: Journal of Neuroscience

Natalie E. Adams, Laura E. Hughes, Holly N. Phillips, Alexander D. Shaw, Alexander G. Murley, David Nesbitt, Thomas E. Cope, W. Richard Bevan-Jones, Luca Passamonti and James B. Rowe

8 January 2020

To bridge the gap between preclinical cellular models of disease and in vivo imaging of human cognitive network dynamics, there is a pressing need for informative biophysical models. Here the researchers assessed dynamic causal models (DCM) of cortical network responses, as generative models of magnetoencephalographic observations during an auditory oddball roving paradigm in healthy adults.

They demonstrated the facility of conductance-based neural mass mean-field models, incorporating local synaptic connectivity, to investigate laminar-specific and GABAergic mechanisms of the auditory response. The neuronal model accurately recapitulated the observed magnetoencephalographic data. Using parametric empirical Bayes for optimal model inversion across both drug sessions, they identified the effect of tiagabine on GABAergic modulation of deep pyramidal and interneuronal cell populations and found a transition of the main GABAergic drug effects from auditory cortex in standard trials to prefrontal cortex in deviant trials.

The successful integration of pharmaco- magnetoencephalography with dynamic causal models of frontotemporal networks provides a potential platform on which to evaluate the effects of disease and pharmacological interventions.

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Publication: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

Carolin Koriath, Tammaryn Lashley, William Taylor, Ronald Druyeh, Athanasios Dimitriadis, Nicola Denning, Julie Williams, Jason D. Warren, Nick C. Fox, Jonathan M. Schott, James B. Rowe, John Collinge, Jonathan D. Rohrer, Simon Mead

19 March 2019

Apolipoprotein E (ApoE) is the most important genetic risk factor for Alzheimer’s disease (AD), with ApoE4 thought to enhance and accelerate amyloid‐β (Aβ) pathology. ApoE4 has recently been described to increase neurodegeneration in a mouse model of frontotemporal dementia (FTD), in vitro, and in patients, demonstrating that ApoE4 modifies tauopathy independently of Aβ. This raises the question whether ApoE genotype also modifies the clinical phenotype in patients with FTD with tau pathology.

The ApoE4 genotype lowered age at onset in patients with FTD and tau pathology, particularly once accounting for confounding effects of Aβ pathology.

The researchers conclude that ApoE4 accelerates neurodegeneration in FTD patients with MAPT mutations or FTLD‐tau pathology, independent of Aβ.

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Publication: Journal of Neurology Neurosurgery and Psychiatry

Edwin Jabbari, John Woodside, Tong Guo, Nadia K Magdalinou, Viorica Chelban, Dilan Athauda, Andrew J Lees, Thomas Foltynie, Henry Houlden, Alistair Church, Michele TM Hu, James B Rowe, Henrik Zetterberg, Huw R Morris

13 March 2019

The high degree of clinical overlap between atypical parkinsonian syndromes (APS) and Parkinson’s disease (PD) makes diagnosis challenging. The researchers aimed to identify novel diagnostic protein biomarkers of APS using multiplex proximity extension assay (PEA) testing.

The biological processes regulated by the significant proteins include cell differentiation and immune cell migration. Delta and notch-like epidermal growth factor-related receptor (DNER) had the strongest effect size in APS versus controls and APS versus PD analyses. DNER is highly expressed in substantia nigra and is an activator of the NOTCH1 pathway which has been implicated in the aetiology of other neurodegenerative disorders including Alzheimer’s disease.

PEA testing has identified potential novel diagnostic biomarkers of APS.

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Publication: Journal of Neurology

David J. Lewis-Smith, Noham Wolpe, Boyd C. P. Ghosh & James B. Rowe

9 January 2020

Alien limb refers to movements that seem purposeful but are independent of patients’ reported intentions. Alien limb often co-occurs with apraxia in the corticobasal syndrome, and anatomical and phenomenological comparisons have led to the suggestion that alien limb and apraxia may be causally related as failures of goal-directed movements. Here, the researchers characterised the nature of alien limb symptoms in patients with the corticobasal syndrome and their relationship to limb apraxia.

Twenty-eight patients with corticobasal syndrome (93%) demonstrated significant apraxia and this was often asymmetrical, with the left hand preferentially affected in 23/30 (77%) patients. Moreover, 25/30 (83%) patients reported one or more symptoms consistent with alien limb. The range of these phenomena was broad, including changes in the sense of ownership and control as well as unwanted movements.

Regression analyses showed no significant association between the severity of limb apraxia and either the occurrence of an alien limb or the number of alien limb phenomena reported. Bayesian estimation showed a low probability for a positive association between alien limb and apraxia, suggesting that alien limb phenomena are not likely to be related to severity apraxia. The results shed light on the phenomenology of these disabling and as yet untreatable clinical features, with relevance to theoretical models of voluntary action.

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