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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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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Validation of the new pathology staging system for progressive supranuclear palsy

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.

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Validation of the new pathology staging system for progressive supranuclear palsy

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.

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Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

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.

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Imaging tau burden in dementia with Lewy bodies using [18F]-AV1451 positron emission tomography

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.

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GABA and glutamate deficits from frontotemporal lobar degeneration are associated with disinhibition

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.

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