Peripheral innate immunophenotype in neurodegenerative disease: blood-based profiles and links to survival

Publication: Nature

Alexandra Strauss, Peter Swann, Stacey L. Kigar, Rafailia Christou, Natalia Savinykh Yarkoni, Lorinda Turner, Alexander G. Murley, Leonidas Chouliaras, Noah Shapiro, Nicholas J. Ashton, George Savulich, W. Richard Bevan-Jones, Ajenthan Surendranthan, Kaj Blennow, Henrik Zetterberg, John T. O’Brien, James B. Rowe & Maura Malpetti

29 October 2024

Summary

The innate immune system plays an integral role in the progression of many neurodegenerative diseases. In addition to central innate immune cells (e.g., microglia), peripheral innate immune cells (e.g., blood monocytes, natural killer cells, and dendritic cells) may also differ in these conditions. However, the characterization of peripheral innate immune cell types across different neurodegenerative diseases remains incomplete. This study aimed to characterize peripheral innate immune profiles using flow cytometry for immunophenotyping of peripheral blood mononuclear cells.

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Quantitative susceptibility mapping at 7 T in COVID-19: brainstem effects and outcome associations 

Publication: Brain

Catarina Rua, Betty Raman, Christopher T Rodgers, Virginia F J Newcombe, Anne Manktelow, Doris A Chatfield, Stephen J Sawcer, Joanne G Outtrim, Victoria C Lupson, Emmanuel A Stamatakis, Guy B Williams, William T Clarke, Lin Qiu, Martyn Ezra, Rory McDonald, Stuart Clare, Mark Cassar, Stefan Neubauer, Karen D Ersche, Edward T Bullmore, David K Menon, Kyle Pattinson, James B Rowe 

08 October 2024

Summary

Damage to the brainstem – the brain’s ‘control centre’ – is behind long-lasting physical and psychiatric effects of severe Covid-19 infection, a study suggests.

Using ultra-high-resolution scanners that can see the living brain in fine detail, researchers from the Universities of Cambridge and Oxford and supported by NIHR Cambridge and Oxford BRCs, were able to observe the damaging effects Covid-19 can have on the brain. Read the full news story.

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Mitochondrial complex I activity in microglia sustains neuroinflammation

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.

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Estimating demand for potential disease-modifying therapies for Alzheimer’s disease in the UK

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.

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Locus coeruleus integrity is linked to response inhibition deficits in Parkinson’s disease and progressive supranuclear palsy

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.

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The use of neuroimaging techniques in the early and differential diagnosis of dementia

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.

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Mortality rates and proximal causes of death in patients with Lewy body dementia versus Alzheimer’s disease: A longitudinal study using secondary care mental health records

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

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Microglial activation in the frontal cortex predicts cognitive decline in frontotemporal dementia

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.

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Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer’s disease

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

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Neurophysiological consequences of synapse loss in progressive supranuclear palsy.

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.

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