Publications

Publication: Nature

L. Peruzzotti-Jametti, C. M. Willis, G. Krzak, R. Hamel, L. Pirvan, R.-B. Ionescu, J. A. Reisz, H. A. Prag, M. E. Garcia-Segura, V. Wu, Y. Xiang, B. Barlas, A. M. Casey, A. M. R. van den Bosch, A. M. Nicaise, L. Roth, G. R. Bates, H. Huang, P. Prasad, A. E. Vincent, C. Frezza, C. Viscomi, G. Balmus, Z. Takats, J. C. Marioni, A. D’Alessandro, M. P. Murphy, I. Mohorianu & S. Pluchino

13 March 2024

Summary

Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species.

Publication: The British Journal of Psychiatry

Axel A. S. Laurell, Ashwin V. Venkataraman, Tatjana Schmidt, Marcella Montagnese, Christoph Mueller,
Robert Stewart, Jonathan Lewis, Clare Mundell, Jeremy D. Isaacs, Mani S. Krishnan, Robert Barber, Timothy Rittman and Benjamin R. Underwood

18 January 2024

Summary

Clinical researchers at Cambridgeshire and Peterborough NHS Foundation Trust and South London and Maudsley NHS Foundation Trust have collaborated to model how many patients might receive new treatments for Alzheimer’s disease currently under review.

Using data on eligible patients from both Trusts and scaling up, the team estimate that a maximum of 30,000 people using dementia services around the country would be suitable for these potential treatments and that NHS providers could provide them on a small scale if approved. Read the full news story.

Publication: Journal of Neuroscience

Rong Ye, Frank H. Hezemans, Claire O’Callaghan, Kamen A. Tsvetanov, Catarina Rua, P. Simon Jones, Negin Holland, Maura Malpetti, Alexander G. Murley, Roger A. Barker, Caroline H. Williams-Gray, Trevor W. Robbins, Luca Passamonti and James B. Rowe

5 September 2023

Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals and are linked with worse prognosis, and lack improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus (LC) noradrenergic system.

Here we test the hypothesis that structural variation of the LC explains response inhibition deficits in PSP and PD. Twenty-four people with idiopathic PD, 14 with PSP-Richardson’s syndrome, and 24 age- and sex-matched controls undertook a stop-signal task and ultrahigh field 7T magnetisation-transfer-weighted imaging of the LC. Parameters of ‘race models’ of go- versus stop-decisions were estimated using hierarchical Bayesian methods to quantify the cognitive processes of response inhibition. We tested the multivariate relationship between LC integrity and model parameters using partial least squares. Both disorders impaired response inhibition at the group level. PSP caused a distinct pattern of abnormalities in inhibitory control with a paradoxically reduced threshold for go responses, but longer non-decision times, and more lapses of attention.

The variation in response inhibition correlated with the variability of LC integrity across participants in both clinical groups. Structural imaging of the LC, coupled with behavioural modelling in parkinsonian disorders, confirms that LC integrity is associated with response inhibition and LC degeneration contributes to neurobehavioural changes. The noradrenergic system is therefore a promising target to treat impulsivity in these conditions. The optimisation of noradrenergic treatment is likely to benefit from stratification according to LC integrity.

Publication: Molecular Psychiatry

Dr Leonidas Chouliaras, Professor John T. O’Brien

22 August 2023

Early and accurate diagnosis of dementia subtype is critical to improving clinical care and developing better treatments. Structural and molecular imaging has contributed to a better understanding of the pathophysiology of neurodegenerative dementias and is increasingly being adopted into clinical practice for early and accurate diagnosis.

In this review we summarise the contribution imaging has made with particular focus on multimodal magnetic resonance imaging (MRI) and positron emission tomography imaging (PET). Structural MRI is widely used in clinical practice and can help exclude reversible causes of memory problems but has relatively low sensitivity for the early and differential diagnosis of dementia subtypes. 

F-fluorodeoxyglucose PET has high sensitivity and specificity for AD and FTD, while PET with ligands for amyloid and tau can improve the differential diagnosis of AD and non-AD dementias, including recognition at prodromal stages. Dopaminergic imaging can assist with the diagnosis of LBD. The lack of a validated tracer for α-synuclein or TAR DNA-binding protein 43 (TDP-43) imaging remain notable gaps, though work is ongoing.

Emerging PET tracers such as C-UCB-J for synaptic imaging may be sensitive early markers but overall larger longitudinal multi-centre cross diagnostic imaging studies are needed.

Publication: International Journal Geriatric Psychiatry

Anne D. Kershenbaum, Annabel C. Price, Rudolf N. Cardinal, Shanquan Chen, James M. Fitzgerald, Jonathan Lewis, Sinéad Moylett, John T. O’Brien

19 May 2023

Summary

Survival is shorter in Lewy body dementia (LBD, referring to both Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB)) compared with Alzheimer’s disease (AD), but the reasons for this difference are not well established.

Researchers identified cohorts of patients with dementia (male and female AD, PDD, and DLB dementia groups) referred into mental health services and linked to National Health Service (NHS) Hospital Episode Statistics and the Office for National Statistics to identify death dates and proximal cause of death. Among patients with DLB and PDD compared to AD ,those with PDD, especially males with PDD, had the highest hazard ratio for death. Aspiration pneumonia and nervous system causes of death accounted for a significant proportion of the excess deaths in the male PDD group compared to the male AD group. Compared with AD, hazard ratios for nervous system causes of death were significantly elevated in all LBD groups. A range of cause‐of‐death categories were significantly more frequent across the LBD groups, with aspiration pneumonia ,genitourinary causes and other respiratory causes elevated in more than one group

Publication: Brain

Maura Malpetti, Thomas E. Cope, Duncan Street, P. Simon Jones, Frank H. Hezemans, Elijah Mak, Kamen A. Tsvetanov, Timothy Rittman, W. Richard Bevan-Jones, Karalyn Patterson, Luca Passamonti, Tim D. Fryer, Young T. Hong, Franklin I. Aigbirhio, John T. O’Brien and James B. Rowe

08 March 2023

Summary

Brain scans like PET enable the visualisation and quantification of brain inflammation, which is an important and common pathological feature in dementia. Using PET we found that high levels of inflammation in frontal brain regions in people with frontotemporal dementia is associated with faster decline in their thinking performance over time. Our results highlight the potential for immunomodulatory treatment strategies in frontotemporal dementia.

Publication: Science Translational Medicine

Ashwin V. Venkataraman, Ayla Mansurgaia, Rizzo Courtney, Bishop, Yvonne Lewis, Ece Kocagoncu, Anne Lingford-Hughes, Mickael Huibanjan Passchier, James B. Rowe, Hideo Tsukada, David J. Brooks, Laurent Martarello, Robert A. Comley, Laigao Chen, Adam J.Schwarz, Richard Hargreaves, Roger N. Gunn, Eugenii A. Rabiner and Paul M. Matthews

18 August 2022

Summary 

Researchers explored whether widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer’s Disease

Publication: MedRxiv

Natalie E Adams, Amirhossein Jafarian, Alistair Perry, Matthew Rouse, Alexander D Shaw, Alexander G Murley,   Thomas E Cope, W Richard Bevan-Jones, Luca Passamonti, Duncan Street, Negin Holland, David Nesbitt, Laura E Hughes,   Karl J Friston, James RoweNatalie E Adams, Amirhossein Jafarian, Alistair Perry, Matthew Rouse,   Alexander D Shaw, Alexander G Murley, Thomas E Cope, W Richard Bevan-Jones, Luca Passamonti, Duncan Street,   Negin Holland, David Nesbitt, Laura E Hughes, Karl J Friston, James Rowe

23 June 2022

Summary

Synaptic loss occurs early in many neurodegenerative diseases and contributes to cognitive impairment even in the absence of gross atrophy. Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. Researchers advocate that biophysical models of neurophysiology offer both a bridge from clinical to preclinical models of pathology, and quantitative assays for experimental medicine.

Publication: Nature Neuroscience

Andrea I. Luppi, Pedro A. M. Mediano, Fernando E. Rosas, Negin Holland, Tim D. Fryer, John T. O’Brien, James B. Rowe, David K. Menon, Daniel Bor & Emmanuel A. Stamatakis

26 May 2022

Researchers investigated functional interactions between brain regions into synergistic and redundant components, revealing their information-processing roles.

Publication: BMJ Journal of Neurology, Neurosurgery and Psychiatry

Leonidas Chouliaras, Alan Thomas, Maura Malpetti, Paul Donaghy, Joseph Kane, Elijah Mak, George Savulich, Maria A Prats-Sedano, Amanda J Heslegrave, Henrik Zetterberg, Li Su, James Benedict Rowe, John O’Brien

27 January 2022

Summary

This longitudinal study compared emerging plasma biomarkers for neurodegenerative disease between controls, patients with Alzheimer’s disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). This large study shows the role of plasma biomarkers in differentiating patients with different dementias, and at monitoring longitudinal change.

Publication: Journal of Nuclear Medicine

Maura Malpetti, Sanne S Kaalund, Kamen A Tsvetanov, Timothy Rittman, Mayen Briggs, Kieren Allinson, Luca Passamonti, Negin Holland, P Simon Jones, Tim D Fryer, Young T Hong, Antonina Kouli, Richard Bevan-Jones, Elijah Mak, George Savulich, Maria Grazia Spillantini, Franklin Aigbirhio, Caroline H Williams-Gray, John T O’Brien and James B Rowe

18 November 2021

Summary

Progressive brain diseases like dementia and Parkinson’s disease move through stages. A new system to stage the dementia-parkinsonian disease known as Progressive Supranuclear Palsy (PSP) has been developed in 2020.  In 2021, researchers validated the new scheme at the Cambridge Brain Bank, looking at the disease severity at the end of life. Researchers wanted to know how the disease progresses and to stop it.

Researchers used a PET scan with a chemical “dye” called 18F-flortaucipi to measure PSP. Despite high hopes for PET using this dye to measure the burden of PSP, when the study began, the results of the study are clear – it does not support the staging of disease, either in lifetime or in terms of outcomes of the illness. 18F-Flortaucipir PET is successfully used in other diseases, like Alzheimer’s, but it cannot be used for PSP staging.

Publication: Journal of Parkinson's Disease

Roger Barker, Danielle Daft, Emma Cutting

01 April 2021

Summary

This is an opinion article on the use of advanced therapy medicinal products in Parkinson’s disease, and how they can be taken into the clinic.

Publication: Neurobiology of Aging

David JWhiteside, P. Simon Jones, Boyd C P Ghosh, Ian Coyle-Gilchrist, Alexander Gerhard, Michele T. Hu, Johannes C Klein, P. Nigel Leigh, Alastair Church, David J Burn, Huw R Morris, James B Rowe, TimothyRittman

16 July 2021

Summary

This study investigated patterns of brain activity at rest in the neurodegenerative disease progressive supranuclear palsy (PSP).

The study found that participants with PSP spend more time than individuals without the disease in certain brain states, meaning their brain activity was less flexible and less efficient than normal. The time spent in these brain states was more apparent in participants who were more severely affected.

The changes in the brain’s activity did not only involve regions of the brain that are most affected by PSP, meaning that effect of the tau protein pathology of PSP has consequences across the whole brain, even where it may appear normal on a scan or have no tau pathology.

Publication: Annals of Clinical and Translational Neurology

Maura Malpetti, , Negin Holland, P. Simon Jones, Rong Ye, , Thomas E. Cope, Tim D. Fryer, Young T. Hong, George Savulich, Timothy Rittman, Luca Passamonti, Elijah Mak, Franklin I. Aigbirhio, John T. O’Brien, & James B. Rowe

16 June 2021

Summary

Brain cells communicate via special connections called synapses. The loss of these synapses is common and early in dementia. We can now measure the amount of synapses across the brain, in people, with a brain scanning technique called positron emission tomography.

Researchers studied healthy adults who were at risk of developing dementia because of a mutation in a gene called C9orf72. They found that synapse loss was already present many years before symptoms were expected, especially in a part of the brain called the thalamus. Such early pre-symptomatic changes are vital to measure, in order to test preventative treatments to step dementia in people at high genetic risk

Publication: Geriatric Psychiatry

Kathy Y. Liu, Robert Howard, Sube Banerjee, Adelina Comas-Herrera, Joanne Goddard, Martin Knapp, Gill Livingston, Jill Manthorpe, John T. O’Brien, Ross W. Paterson, Louise Robinson, Martin Rossor, James B. Rowe, David J. Sharp, Andrew Sommerlad, Aida Suárez-González, Alistair Burns

16 May 2021

In response to a commissioned research update on dementia during the COVID-19 pandemic, a UK-based working group, comprising dementia researchers from a range of fields and disciplines, aimed to describe the impact of the pandemic on dementia wellbeing and identify priorities for future research.

Publication: NeuroImage: Clinical

Martina Bocchetta, Emily G. Todd, Georgia Peakman, David M. Cash, Rhian S. Convery, Lucy L.Russell, David L. Thomas, Juan Eugenio Iglesias, John C.van Swieten, Lize C. Jiskootf, Harro Seelaar, Barbara Borronig, Daniela Galimbertihi, Raquel Sanchez-Vallej, Robert Laforce Jr, Fermin Morenol, Matthis Synofzik, Caroline Graffno, Mario Masellis, Maria Carmela Tartaglia, James B.Rower, Rik Vandenberghes, Elizabeth, Finger, Fabrizio Tagliaviniu, Alexandrede Mendonçav, Isabel Santanaw, Chris R.Butlerx, Simon Ducharmey, Alexander Gerhardza,  AdrianDanek, JohannesLevina,  Markus Ottoac, Sandro Sorbiad, Isabelle Le Beraeafag, Florence Pasquierahaiaj, Jonathan D.Rohrera.

29 March 2021

Summary

Studies have previously shown evidence for presymptomatic cortical atrophy in genetic FTD. Whilst initial investigations have also identified early deep grey matter volume loss, little is known about the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups.

Publication: Journal of Neurology, Neurosurgery and Psychiatry

Maura Malpetti, Luca Passamonti, P Simon Jones, Duncan Street, Timothy Rittman, Timothy D Fryer, Young T Hong, Patricia Vàsquez Rodriguez,  W Richard Bevan-Jones, Franklin I Aigbirhio, John T O’Brien, James B Rowe

17 March 2021

Summary:

Progressive supranuclear palsy (PSP) causes dementia and movement disorders. Researchers show that it is associated with brain inflammation, in addition to tau protein build-up. Using a PET (Positron Emission Tomography ) brain scan they were able to map the presence of inflammation in the brain of living volunteers with PSP, who were followed up for several years.

Publication: Acta Neuropathologica

Mayen Briggs, Kieren Allinson, Maura Malpetti, Maria G. Spillantini, James B. Rowe, Sanne S. Kaalund

16 March 2021

Summary:

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder. Researchers test the new PSP pathology staging system in an independent series of PSP, and test the potential association between pathology stage and clinical severity at death.

Researchers show that those with a higher pathology stage – more widespread pathology, at post mortem also scored higher on disease severity scales in life.

Publication: Brain

Claire O’Callaghan, Frank H Hezemans, Rong Ye, Catarina Rua, P Simon Jones, Alexander G Murley, Negin Holland, Ralf Regenthal, Kamen A Tsvetanov, Noham Wolpe, Roger A Barker, Caroline H Williams-Gray, Trevor W Robbins, Luca Passamonti, James B Rowe

30 March 2021

Summary:

Drugs that increase the brain’s noradrenaline can improve cognition in Parkinson’s disease. A challenge remains to identify those who will most benefit from noradrenergic drugs. We show that drug response depends on integrity of the locus coeruleus nucleus. This will inform clinical trial patient selection and treatment.

Publication: Acta Neuropathologica

Mayen Briggs, Kieren Allinson, Maura Malpetti, Maria G. Spillantini, James B. Rowe, Sanne S. Kaalund

28 March 2021

The research team validated a new system for staging brain pathology at post mortem in a devastating neurodegenerative diseases called progressive supranuclear palsy (PSP).

They show that those with a higher pathology stage, i.e. more widespread pathology, at post mortem also scored higher on disease severity scales in life.

Standardised staging systems provides a common language for neuropathologists on what is considered mild, moderate and severe pathology. They can be used to test if treatments impact the severity of pathology, and make it easier to compare results between studies.

Showing that the pathology stage is associated with clinical severity, the next step will be to try and replicate the pathology staging in vivo using brain imaging, e.g. PET, to test if researchers can track pathogenesis alongside clinical disease progression.

Publication: Journal of Neurology, Neurosurgery and Psychiatry

9 February 2021

Summary

Researchers looked at the clinical features associated with survival in the syndromes related to frontotemporal lobar degeneration, including frontotemporal dementia, progressive suprnuclear palsy and corticobasal syndrome.

They found that behavioural disturbance, including impulsivity and apathy, is associated with reduced functionally independent survival.

Publication: Neurobiology of Ageing

ElijahMaka, NeginHolland, P. Simon Jones, George Savulich, Audrey Lowa, Maura Malpetti, Sanne Kaalund, Luca Passamonti, Timothy Rittman, Rafael Romero-Garciaa, Roido Manavakic, Guy B.Williams, Young T.Hong, Ti m D. Fryerb, Franklin I. Aigbirhio, John O’Brien, James Rowe

30 January 2021

Summary

Researchers found in neurodegenerative disorders of Progressive Supranuclear Palsy and Corticobasal Degeneration, the core communication units of the brain (present on nerve cell ‘bodies’ and ‘tails’) are tightly coupled together and are both significantly reduced by the disease process. The research shows changes in the brain of patients with neurodegenerative disorders and can help inform the design of clinical trials

Publication: Alzheimer's & Dementia: The Journal of the Alzheimer's Association

Maura Malpetti, P. Simon Jones, Kamen A. Tsvetanov, Timothy Rittman, John C. van Swieten, Barbara Borroni, Raquel Sanchez‐Valle, Fermin Moreno, Robert Laforce, Caroline Graff, Matthis Synofzik, Daniela Galimberti, Mario Masellis, Maria Carmela Tartaglia, Elizabeth Finger, Rik Vandenberghe, Alexandre de Mendonça, Fabrizio Tagliavini Isabel Santana, Simon Ducharme, Chris R. Butler, Alexander Gerhard, Johannes Levin, Adrian Danek, Markus Otto,Giovanni B. Frisoni, Roberta Ghidoni, Sandro Sorbi,Carolin Heller,Emily G. Todd, Martina Bocchetta, David M. Cash,Rhian S. Convery, Georgia Peakman, Katrina M. Moore, Jonathan D. Rohrer, Rogier A. Kievit, James B. Rowe

15 December 2020

Summary:

Apathy – a lack of interest or motivation – could predict the onset of some forms of dementia many years before symptoms start, offering a ‘window of opportunity’ to treat the disease at an early stage. Apathy changes decades before dementia onset and is driven by early brain shrinkage in individuals at risk of dementia. Early signs of apathy before dementia predict a faster decline in cognitive performance. Apathy can point to early brain changes even years before dementia symptoms begin, providing a window of opportunity to intervene and slow disease progression. Read the full news story.

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: Journal of Neurology, Neurosurgery, and 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

Summary:

Using PET imaging, researchers looked at neuro inflammation and abnormal growth of protein for patients with frontotemporal dementia (FTD). They found Familial FTD was associated with neuroinflammation across all genes and also reflected clinical heterogeneity. This research will be able to help to further understand the disease and in particular around the immune system to help with treatments and prevention.

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

Progressive Supranuclear Palsy (PSP) is associated with tau-protein aggregation and neuroinflammation. In this study the research team mapped these features in the brain of living patients with a brain-scanning technique called positron emission tomography (PET). They examined the relationship between tau pathology and inflammation, and their association with clinical severity.

Tau pathology and neuroinflammation occur in the same parts of the brain of patients with PSP, and they are both linked to the severity of symptoms.

Following this study the research team suggests 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 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: 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.

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: 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.

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.

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.

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.

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.

Publication: Journal of Neurology, Neurosurgery and Psychiatry

Jonathan Tay, Robin G Morris, Anil M Tuladhar, Masud Husain, Frank-Erik de Leeuw, Hugh S Markus

July 2020

Summary:

Cerebral small vessel disease (SVD) is the leading vascular cause of dementia and plays a major role in cognitive decline and mortality.

This research aimed to determine whether apathy or depression predicts all-cause dementia in SVD patients.

Using two prospective cohort studies of SVD, the researchers looked at changes in apathy and depression in 104 patients to predict dementia.

The research indicated that while increasing apathy was associated with dementia, baseline depression and change in depression did not predict dementia.

The researchers concluded that apathy, but not depression, may be an early sign of dementia in SVD, and that this may be useful in identifying at-risk individuals.

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: 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

Summary

In this study researchers looked at the loss of synapses in two tau-related neurodegenerative diseases (progressive supranuclear palsy and corticobasal syndrome) and the effect of this loss on cognition. The research was done using a novel PET radioligand, [11C]UCB-J.

They found a profound loss of synapses in all areas of the brain, beyond the effect of volume loss. This synaptic loss negatively correlated with disease severity and positively witih cognition.

These findings are key in identifying early steps in the pathology of neurodegeneration, and offer therapeutic targets for future clinical trials.

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.

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.

Publication: Brain

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

07 May 2020

Summary:

Alzheimer’s disease is a condition associated with an ongoing decline of the brain functioning correctly. It can affect loss of memory, language and completing everyday tasks.

Researchers having been investigating the brains functionality, and whether they could help clinicians calculate how a patient will progress with their dementia.

Using an imaging machine called PET (positron emission tomography) they were able to take brain scans and detect the build-up of ‘junk proteins’ in the brain alongside brain inflammation and shrinkage. It could help predict how fast or slow and individual will progress with their dementia.

The PET scans could predict faster cognitive decline in patients and they were more accurate predictors than MRI measures of brain shrinkage.

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.

Publication: Cortex

Thomas E. Cope, Yury Shtyrov, Lucy J. MacGregor, Rachel Holland, Friedemann Pulvermüller, James B. Rowe, Karalyn Patterson

1 May 2020

In the healthy human brain, the processing of language is strongly lateralised, usually to the left hemisphere, while the processing of complex non-linguistic sounds recruits brain regions bilaterally. Here the researchers asked whether the anterior temporal lobes, strongly implicated in semantic processing, are critical to this special treatment of spoken words. Nine patients with semantic dementia (SD) and fourteen age-matched controls underwent magnetoencephalography and structural MRI.

Source reconstructions confirmed recruitment of right-sided analogues of language regions in SD: atrophy of anterior temporal lobes was associated with increased activity in right temporal pole, middle temporal gyrus, inferior frontal gyrus and supramarginal gyrus.

Overall, the results indicate that anterior temporal lobes are necessary for normal and efficient lateralised processing of word identity by the language network.

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.

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.

Publication: Journal of Neurology

Alexander G. Murley, P. Simon Jones, Ian Coyle Gilchrist, Lucy Bowns, Julie Wiggins, Kamen A. Tsvetanov & James B. Rowe

10 April 2020

Widespread metabolic changes are seen in neurodegenerative disease and could be used as biomarkers for diagnosis and disease monitoring. They may also reveal disease mechanisms that could be a target for therapy. In this study the researchers looked for blood-based biomarkers in syndromes associated with frontotemporal lobar degeneration (FTLD).

Forty-nine of 842 metabolites were significantly altered in frontotemporal lobar degeneration syndromes (after false-discovery rate correction for multiple comparisons). These were distributed across a wide range of metabolic pathways including amino acids, energy and carbohydrate, cofactor and vitamin, lipid and nucleotide pathways. The metabolomic profile supported classification between frontotemporal lobar degeneration syndromes and controls with high accuracy (88.1–96.6%) while classification accuracy was lower between the frontotemporal lobar degeneration syndromes (72.1–83.3%). One metabolic profile, comprising a range of different pathways, was consistently identified as a feature of each disease versus controls: the degree to which a patient expressed this metabolomic profile was associated with their subsequent survival (hazard ratio 0.74 [0.59–0.93], p = 0.0018).

The metabolic changes in FTLD are promising diagnostic and prognostic biomarkers. Further work is required to replicate these findings, examine longitudinal change, and test their utility in differentiating between FTLD syndromes that are pathologically distinct but phenotypically similar.

Publication: Frontiers in Neuroscience

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

19 March 2020

The peak width of skeletonized mean diffusivity (PSMD) has been proposed as a fully automated imaging marker of relevance to cerebral small vessel disease (SVD). The researchers assessed PSMD in relation to conventional SVD markers, global measures of neurodegeneration, and cognition.

PSMD was associated with global and regional SVD measures, especially WMH and microbleeds. Dominance analysis demonstrated that among SVD markers, WMH was the strongest predictor of PSMD. Furthermore, PSMD was more closely associated to WMH than with GM and WM volumes.

This new measure appears to be a marker of diffuse brain injury, largely due to vascular pathology, and may be a useful and convenient metric of overall cerebrovascular burden.

Publication: Neurobiology of Aging

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

17 March 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.

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. Similarly, higher Tau burden was associated with decreases in both local and global efficiency, especially in the gamma band.

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

Publication: Nature Communications

Sanne Simone Kaalund, Luca Passamonti, Kieren S. J. Allinson, Alexander G. Murley, Trevor W. Robbins, Maria Grazia Spillantini and James B. Rowe

4 February 2020

Summary:

The locus coeruleus is the major source of noradrenaline to the brain and contributes to a wide range of physiological and cognitive functions. Neurodegeneration and pathological aggregation of tau protein in the locus coeruleus are early features of progressive supranuclear palsy (PSP). It is proposed to contribute to the clinical expression of the disease, including the PSP Richardson’s syndrome. Researchers investigated whether the tau and neuronal loss are associated with clinical heterogeneity and severity in PSP.

Publication: Acta Neuropathologica Communications

Sanne Simone Kaalund, Luca Passamonti, Kieren S. J. Allinson, Alexander G. Murley, Trevor W. Robbins, Maria Grazia Spillantini & James B. Rowe

4 February 2020

The noradrenergic deficit in the locus coeruleus is a candidate target for pharmacological treatment. Recent developments in ultra-high field magnetic resonance imaging to quantify in vivo structural integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in Progressive supranuclear palsy (PSP).

Degeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. Integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in PSP.

Publication: Acta Neuropathologica Communications

Sanne Simone Kaalund, Luca Passamonti, Kieren S. J. Allinson, Alexander G. Murley, Trevor W. Robbins, Maria Grazia Spillantini & James B. Rowe

4 February 2020

The locus coeruleus is the major source of noradrenaline to the brain and contributes to a wide range of physiological and cognitive functions including arousal, attention, autonomic control, and adaptive behaviour. Neurodegeneration and pathological aggregation of tau protein in the locus coeruleus are early features of progressive supranuclear palsy (PSP). This pathology is proposed to contribute to the clinical expression of disease, including the PSP Richardson’s syndrome. The researchers tested the hypothesis that tau pathology and neuronal loss are associated with clinical heterogeneity and severity in PSP.

They found an average 49% reduction of pigmented neurons in PSP patients relative to controls. The loss of pigmented neurons correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death. The degree of neuronal loss was negatively associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions.

Degeneration and tau pathology in the locus coeruleus are related to clinical heterogeneity of PSP. The noradrenergic deficit in the locus coeruleus is a candidate target for pharmacological treatment. Recent developments in ultra-high field magnetic resonance imaging to quantify in vivo structural integrity of the locus coeruleus may provide biomarkers for noradrenergic experimental medicines studies in PSP.

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.

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.

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.

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.

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.

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.

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.

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

Audrey Low, Elijah Mak, Maura Malpetti, Leonidas Chouliaras, Nicolas Nicastro, Li Sua, Negin Holland, Timothy Rittman, Patricia Vázquez Rodríguez, Luca Passamonti, W Richard Bevan-Jones, PP Simon Jones, James B.Rowe, John T.O’Brien

1 December 2019

Widespread cortical asymmetries have been identified in Alzheimer’s disease (AD), but thalamic asymmetries and their relevance to clinical severity in AD remain unclear.

This research discovered that although overall asymmetry of the thalamus did not differ between groups, greater leftward lateralization of atrophy in the ventral nuclei was demonstrated in AD, compared with controls and amyloid-positive mild cognitive impairment. Increased posterior ventrolateral and ventromedial nuclei asymmetry were associated with worse cognitive dysfunction, informant-reported neuropsychiatric symptoms, and functional ability.

Leftward ventral thalamic atrophy was associated with disease severity in AD. The findings suggest the clinically relevant involvement of thalamic nuclei in the pathophysiology of AD.

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.

Publication: J Neurology Neurosurgery Psychiatry

Denis HL, Lamontagne-Proulx J, St-Amour I, Mason SL, Rowley JW, Cloutier N, et al.

2019 Mar;90(3):272-283

Publication: Annals of Clinical and Translational Neurology

Nicolas Nicastro, Ajenthan Surendranathan, Elijah Mak, James B. Rowe, John T. O’Brien

10 September 2019

There is evidence of increased microglial activation in Parkinson’s disease (PD) as shown by in vivo PET ligand such as 11C‐PK11195. In addition, diffusion tensor imaging (DTI) imaging reveals widespread changes in PD, especially when the associated dementia develops.

The researchers studied five subjects with Parkinson’s disease dementia (PDD). Their findings suggest that while DTI metrics mirror cognitive severity, higher 11C‐PK11195 binding seems to be associated with a relative preservation of both white matter tracts and cognition.

Longitudinal studies are warranted to tackle the complex relationship between microglial activation and structural abnormalities in neurodegenerative conditions.

Publication: Brain Communications

Robin J Borchert, Timothy Rittman, Charlotte L Rae, Luca Passamonti, Simon P Jones, Deniz Vatansever, Patricia Vázquez Rodríguez, Zheng Ye, Cristina Nombela, Laura E Hughes, Trevor W Robbins, James B Rowe

6 September 2019

Parkinson’s disease has multiple detrimental effects on motor and cognitive systems in the brain. In contrast to motor deficits, cognitive impairments in Parkinson’s disease are usually not ameliorated, and can even be worsened, by dopaminergic treatments. Recent evidence has shown potential benefits from restoring other neurotransmitter deficits, including noradrenergic and serotonergic transmission.

The researchers studied global and regional brain network organization using task-free imaging (also known as resting-state), which minimizes performance confounds and the bias towards predetermined networks.

Thirty-three patients with idiopathic Parkinson’s disease were studied three times in a double-blinded, placebo-controlled counter-balanced crossover design, following placebo, 40 mg oral atomoxetine (selective noradrenaline reuptake inhibitor) or 30 mg oral citalopram (selective serotonin reuptake inhibitor).

In patients, atomoxetine improved fluency in proportion to plasma concentration, and improved response inhibition in proportion to increased hub Eigen centrality. Citalopram did not improve fluency or inhibitory control, but its influence on network integration and efficiency depended on disease severity: clustering, modularity and path length increased in patients with milder forms of Parkinson’s disease, but decreased in patients with more advanced disease.

This study supports the use of task-free imaging of brain networks in translational pharmacology of neurodegenerative disorders. The researchers propose that hub connectivity contributes to cognitive performance in Parkinson’s disease, and that noradrenergic treatment strategies can partially restore the neural systems supporting executive function.

Publication: Diagnostics

Jeremy M. Brown, Julie Wiggins, Kate Dawson, Timothy Rittman, James B. Rowe

12 August 2019

This research paper summarises the current status of two novel short cognitive tests (SCT), known as Test Your Memory (TYM) and Test Your Memory for Mild Cognitive Impairment (TYM-MCI). The history of and recent research on the TYM and TYM-MCI are summarised in applications for Alzheimer’s and non-Alzheimer’s dementia and mild cognitive impairment.

In this NIHR Cambridge-BRC funded research, the researchers found out that the TYM test can be used in a general neurology clinic and can help distinguish patients with Alzheimer’s disease (AD) from those with no neurological cause for their memory complaints. An adapted tele-TYM test administered by telephone to patients produces scores which correlate strongly with the clinic-administered Addenbrooke’s Cognitive Examination revised (ACE-R) test and can identify patients with dementia.

This is important because the team showed that patients with AD decline on the TYM test at a rate of 3.6–4.1 points/year.

Publication: Aging Research Reviews

Audrey Low, Elijah Mak, James B.Rowe, Hugh S.Markus, John T. O’Brien

1 August 2019

Inflammation is increasingly implicated as a risk factor for dementia, stroke, and small vessel disease (SVD). However, the underlying mechanisms and causative pathways remain unclear. The researchers systematically reviewed the existing literature on the associations between markers of inflammation and SVD (i.e., white matter hyperintensities (WMH), lacunes, enlarged perivascular spaces (EPVS), cerebral microbleeds (CMB)) in cohorts of older people with good health, cerebrovascular disease, or cognitive impairment.

Evidence from 82 articles revealed relatively robust associations between SVD and markers of vascular inflammation, especially amongst stroke patients, suggesting that alterations to the endothelium and blood-brain barrier may be a driving force behind SVD.

These findings have important implications on interventions, suggesting the potential utility of treatments targeting the brain endothelium and blood brain barrier to combat SVD and associated neurodegenerative diseases.

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.

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.

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.

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.

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.

Publication: Neurobiology of Aging

Rittman T, Borchert R, Jones S, van Swieten J, Borroni B, Galimberti D, et al.

May 2019

Publication: Brain

David Howett, Andrea Castegnaro, Katarzyna Krzywicka, Johanna Hagman, Deepti Marchment, Richard Henson, Miguel Rio, John A King, Neil Burgess, Dennis Chan

May 19

Summary:

This research showed that a virtual reality test of spatial navigation was more effective at identifying patients with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) than gold standard tests of memory and thinking currently used in clinic and research studies. More here

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.

Publication: Journal of Huntington's Disease

Horton MC, Nopoulos P, Nance M, Landwehrmyer GB, Barker RA, Squitieri F, et al.

30 April 2019

Publication: Neurology

Claire J. Lansdall, Ian T.S. Coyle-Gilchrist, Patricia Vázquez Rodríguez, Alicia Wilcox, Eileen Wehmann, Trevor W. Robbins, James B. Rowe

12 April 2019

This research determined the influence of apathy, impulsivity, and behavioral change on survival in patients with frontotemporal dementia, progressive supranuclear palsy, and corticobasal syndrome.

The relationship between apathy and survival highlights the need to develop more effective and targeted measurement tools to improve its recognition and facilitate treatment. The prognostic importance of apathy suggests that neurobehavioral features might be useful to predict survival and stratify patients for interventional trials.

Effective symptomatic interventions targeting the neurobiology of apathy might ultimately also improve prognosis.

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.

Publication: BMJ Open

Koychev I, Lawson J, Chessell T, Mackay C, Gunn R, Sahakian B, et al.

23 March 2019

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.

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.

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.

Publication: Neurology

Traylor M, Tozer DJ, Croall ID, Lisiecka Ford DM, Olorunda AO, Boncoraglio G, et al.

19 February 2019

Publication: Stroke

Drazyk AM, Tan RYY, Tay J, Traylor M, Das T, Markus HS.

14 January 2019

Publication: Annals of Clinical Translational Neurology

Bevan-Jones WR, Cope TE, Jones PS, Passamonti L, Hong YT, Fryer T, et al.

2 January 2019

Publication: Neuroimage

Cury C, Durrleman S, Cash DM, Lorenzi M, Nicholas JM, Bocchetta M, et al.

6 December 2018

Publication: Nature Medicine

Swarup V, Hinz FI, Rexach JE, Noguchi KI, Toyoshiba H, Oda A, et al.

3 December 2018

Publication: Journal of Alzheimer's Disease,

Moylett S, Price A, Cardinal RN, Aarsland D, Mueller C, Stewart R, O’Brien JT.

28 November 2018

Publication: Brain

Surendranathan A, Su L, Mak E, Passamonti L, Hong YT, Arnold R, et al.

6 November 2018

Publication: Nature Communications

Young AL, Marinescu RV, Oxtoby NP, Bocchetta M, Yong K, Firth NC, et al.

15 October 2018

Publication: Cell Metabolism

Son SM, Park SJ, Lee H, Siddiqi F, Lee JE, Menzies FM, et al.

6 September 2018

Publication: European Journal of Neurosciences

Greenland JC, Williams-Gray CH, Barker RA.

30 July 2018

Publication: Nature Communications

Pavel M, Renna M, Park SJ, Menzies FM, Ricketts T, Fullgrabe J, et al.

27 July 2018

Publication: Brain

Sami S, Williams N, Hughes LE, Cope TE, Rittman T, Coyle-Gilchrist ITS, et al.

9 July 2018

Publication: Brain

Hughes LE, Rittman T, Robbins TW, Rowe JB.

9 July 2018

Publication: Nature

Barker RA, Gotz M, Parmar M.

16 May 2018

Publication: Brain

Thomas E Cope, Timothy Rittman, Robin J Borchert, P Simon, JonesDeniz Vatansever, Kieren Allinson Luca Passamonti, Patricia Vazquez Rodriguez, W Richard Bevan-Jones, John T O’Brien, James B Rowe

Publication: J Neurol

Underwood BR, Green-Thompson ZW, Pugh PJ, Lazic SE, Mason SL4, Griffin J, Jones PS, Rowe JB, Rubinsztein DC7,4, Barker RA.

26 October 2017

Publication: International Journal of Neuropsychopharmacology

Publication: British Journal of Psychiatry

Su L, Faluyi YO, Hong T, Fryer D, Mak E, Gabel S, Hayes L, Soteriades S, Williams GB, Arnold R, Passamonti L, Vazquez Rodirguez P, Surendranathan A, Bevan-Jones RW, Coles J, Aigbirhio F, Rowe JB, O’Brien JT

December 2016

Publication: Nature

M Pavel, S Imarisio, FM Menzies, M Jimenez-Sanchez, FH Siddiqi, X Wu, M Renna, CJ O’Kane, DC Crowther, and DC Rubinsztein

8 December 2016

Publication: Mov Disord

Breen DP, Nombela C, Vuono R, Jones PS, Fisher K, Burn DJ, Brooks DJ, Reddy AB, Rowe JB, Barker RA.

31 July 2016

Publication: Mov Disord

Williams-Gray CH, Wijeyekoon R, Yarnall AJ, Lawson RA, Breen DP, Evans JR, Cummins GA, Duncan GW, Khoo TK, Burn DJ, Barker RA; ICICLE-PD study group

31 July 2016

Publication: Brain

Rae CL, Nombela C, Rodríguez PV, Ye Z, Hughes LE, Jones PS, Ham T, Rittman T, Coyle-Gilchrist I, Regenthal R, Sahakian BJ, Barker RA, Robbins TW, Rowe JB.

24 June 2016

Publication: METASTROKE

Dichgans M, Williams J, Lewis CM, Markus HS;

23 February 2016

Publication: J Neurol Neurosurg Psychiatry

Begeti F, Schwab LC, Mason SL, Barker RA.

1 February 2016

Publication: J Neurol Neurosurg Psychiatry

Evans JR, Cummins G, Breen DP, Foltynie T, Mason SL, Brayne CE, Williams-Gray CH, Barker RA.

22 January 2016

Publication: Translational Neuropsychopharmacology

Barnett JH, Blackwell AD, Sahakian BJ & Robbins TW (2016). In: Robbins TW, Sahakian BJ (Eds).

January 2015