The latest list of publications from the NIHR Cambridge Biomedical Research Centre with a brief summary.
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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.View publication
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.View publication
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.View publication
Publication: Cerebral Cortex
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.View publication
Publication: Alzheimer's & Dementia Diagnosis, Assessment & Disease Monitoring
Thilo van Eimeren, Angelo Antonini, Daniela Berg, Nico Bohnen, Roberto Ceravolo, Alexander Drzezga, Günter U. Höglinger, Makoto Higuchi, Stephane Lehericy, Simon Lewis, Oury Monchi, Peter Nestor, Matej Ondrus, Nicola Pavese, María Cecilia Peralta, Paola Piccini, José Ángel Pineda‐Pardo, Irena Rektorová, María Rodríguez‐Oroz, Axel Rominger, Klaus Seppi, A. Jon Stoessl, Alessandro Tessitore, Stephane Thobois, Valtteri Kaasinen, Gregor Wenning, Hartwig R. Siebner, Antonio P. Strafella, James B. Rowe
2 April 2019
Therapeutic strategies targeting protein aggregations are ready for clinical trials in atypical parkinsonian disorders. Therefore, there is an urgent need for neuroimaging biomarkers to help with the early detection of neurodegenerative processes, the early differentiation of the underlying pathology, and the objective assessment of disease progression. However, there currently is not yet a consensus in the field on how to describe utility of biomarkers for clinical trials in atypical parkinsonian disorders.
As a consensus outcome, the researchers described the main challenges in ascribing utility of neuroimaging biomarkers in atypical parkinsonian disorders, and proposed a conceptual framework that includes a graded system for the description of utility of a specific neuroimaging measure. They included separate categories for the ability to accurately identify an intention‐to‐treat patient population early in the disease (Early), to accurately detect a specific underlying pathology (Specific), and the ability to monitor disease progression (Progression).
The researchers suggest that the advancement of standardized neuroimaging in the field of atypical parkinsonian disorders will be furthered by a well‐defined reference frame for the utility of biomarkers. The proposed utility system allows a detailed and graded description of the respective strengths of neuroimaging biomarkers in the currently most relevant areas of application in clinical trials.View publication
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.View publication
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.View publication
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.View publication
Publication: JAMA Neurology
Edwin Jabbari, Negin Holland, Viorica Chelban, P. Simon Jones, Ruth Lamb, Charlotte Rawlinson, Tong Guo, Alyssa A. Costantini, Manuela M. X. Tan, Amanda J. Heslegrave, Federico Roncaroli, Johannes C. Klein, Olaf Ansorge, Kieren S. J. Allinson, Zane Jaunmuktane, Janice L. Holton, Tamas Revesz, Thomas T. Warner, Andrew J. Lees, Henrik Zetterberg, Lucy L. Russell, Martina Bocchetta, Jonathan D. Rohrer, Nigel M. Williams, Donald G. Grosset, David J. Burn, Nicola Pavese, Alexander Gerhard, Christopher Kobylecki, P. Nigel Leigh, Alistair Church, Michele T. M. Hu, John Woodside, Henry Houlden, James B. Rowe, Huw R. Morris
20 December 2019
This research looked at the distinguishing features of progressive supranuclear palsy and corticobasal syndrome subtypes and how they can be distinguished from Parkinson disease.
In this cohort study of 222 patients with atypical parkinsonian syndromes, recently defined progressive supranuclear palsy subtypes are almost as common as classic Richardson syndrome and share midbrain atrophy as a common hallmark. Distinct patterns of clinical trajectory, cognitive profile, serum neurofilament light chain level, genetic, and volumetric magnetic resonance imaging measures helped to distinguish the clinical subtypes of progressive supranuclear palsy and corticobasal syndrome; clinical trajectory and serum neurofilament light chain levels distinguished Parkinson disease from progressive supranuclear palsy and corticobasal syndrome
This study suggests that subtypes of progressive supranuclear palsy and corticobasal syndrome have distinct characteristics that may enhance their early diagnosis.View publication
Publication: The Lancet Neurology
Katrina M Moore, Jennifer Nicholas, Prof Murray Grossman, Corey T McMillan, David J Irwin, Lauren Massimo, PhD et al
3 December 2019
Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, the researchers aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.
The study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership.
Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, this study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.View publication
Publication: The Lancet Neurology
Emma L van der Ende, Lieke H Meeter, Jackie M Poos, Jessica L Panman, Lize C Jiskoot, Elise G P Dopper, Janne M Papma, Frank Jan de Jong, Inge M W Verberk, Prof Charlotte Teunissen, Prof Dimitris Rizopoulos, Carolin Heller, Rhian S Convery, Katrina M Moore, Martina Bocchetta, Mollie Neason, David M Cash, Barbara Borroni, Daniela Galimberti, Raquel Sanchez-Valle, Robert Laforce Jr, Fermin Moreno, Prof Matthis Synofzik, Prof Caroline Graff, Mario Masellis, Maria Carmela Tartaglia, Prof James B Rowe, et al
1 December 2019
Neurofilament light chain (NfL) is a promising blood biomarker in genetic frontotemporal dementia, with elevated concentrations in symptomatic carriers of mutations in GRN, C9orf72, and MAPT. A better understanding of NfL dynamics is essential for upcoming therapeutic trials. The research team aimed to study longitudinal NfL trajectories in people with presymptomatic and symptomatic genetic frontotemporal dementia.
Their findings show the value of blood NfL as a disease progression biomarker in genetic frontotemporal dementia and suggest that longitudinal NfL measurements could identify mutation carriers approaching symptom onset and capture rates of brain atrophy.
This is important because the characterisation of NfL over the course of disease provides valuable information for its use as a treatment effect marker.View publication
Publication: Movement Disorders
Fraser S. Brown, James B. Rowe, Luca Passamonti, Timothy Rittman
6 December 2019
Despite falls being an almost universal clinical feature and central to the presentation and diagnostic criteria of progressive supranuclear palsy, our understanding of falls is surprisingly limited and there are few effective treatment options.
The researchers reviewed current understanding of the pathophysiology of falls, highlighting the roles of the indirect pathway and the pedunculopontine nucleus. They then identified shortcomings in commonly used assessments to measure falls, looked at medical and nonmedical fall prevention strategies, and finally discussed balancing falls risk against promoting independence.
Falls are central to progressive supranuclear palsy presentation and diagnosis. Indirect locomotor and pedunculopontine nucleus dysfunction are thought to be the neural substrate of falls in this condition. Attempts to measure and prevent falls, by medical and nonmedical means, are currently limited. A personalized approach is advocated in the management of falls.View publication