Publications by authors named "Federico Roncaroli"

137 Publications

Early changes in visuospatial episodic memory can help distinguish primary age-related tauopathy from Alzheimer's disease.

Neuropathol Appl Neurobiol 2021 May 9. Epub 2021 May 9.

Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK.

The observation of neurofibrillary tangles (NFTs) without associated amyloid-beta (Aβ) in the brains of cognitively normal and cognitively impaired elderly individuals has, for many years, been a source of discussion and controversy. The term "primary age-related tauopathy" (PART) was introduced in 2014 and consensus guidelines for the condition were published [1]. The clinical manifestations of PART have been described (see [2] for review). A recent molecular imaging study suggested that mesial temporal tau load is associated with a decline in cognitive performance in those with no Aβ pathology [3].
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http://dx.doi.org/10.1111/nan.12726DOI Listing
May 2021

Widespread Decreases in Cerebral Copper Are Common to Parkinson's Disease Dementia and Alzheimer's Disease Dementia.

Front Aging Neurosci 2021 3;13:641222. Epub 2021 Mar 3.

Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Centre for Advanced Discovery & Experimental Therapeutics, School of Medical Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.

Several studies of Parkinson's disease (PD) have reported dysregulation of cerebral metals, particularly decreases in copper and increases in iron in substantia nigra (SN). However, few studies have investigated regions outside the SN, fewer have measured levels of multiple metals across different regions within the same brains, and there are no currently-available reports of metal levels in Parkinson's disease dementia (PDD). This study aimed to compare concentrations of nine essential metals across nine different brain regions in cases of PDD and controls. Investigated were: primary motor cortex (MCX); cingulate gyrus (CG); primary visual cortex (PVC); hippocampus (HP); cerebellar cortex (CB); SN; locus coeruleus (LC); medulla oblongata (MED); and middle temporal gyrus (MTG), thus covering regions with severe, moderate, or low levels of neuronal loss in PDD. Levels of eight essential metals and selenium were determined using an analytical methodology involving the use of inductively-coupled plasma mass spectrometry (ICP-MS), and compared between cases and controls, to better understand the extent and severity of metal perturbations. Findings were also compared with those from our previous study of sporadic Alzheimer's disease dementia (ADD), which employed equivalent methods, to identify differences and similarities between these conditions. Widespread copper decreases occurred in PDD in seven of nine regions (exceptions being LC and CB). Four PDD-affected regions showed similar decreases in ADD: CG, HP, MTG, and MCX. Decreases in potassium and manganese were present in HP, MTG and MCX; decreased manganese was also found in SN and MED. Decreased selenium and magnesium were present in MCX, and decreased zinc in HP. There was no evidence for increased iron in SN or any other region. These results identify alterations in levels of several metals across multiple regions of PDD brain, the commonest being widespread decreases in copper that closely resemble those in ADD, pointing to similar disease mechanisms in both dementias.
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http://dx.doi.org/10.3389/fnagi.2021.641222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966713PMC
March 2021

Imaging of the glioma microenvironment by TSPO PET.

Eur J Nucl Med Mol Imaging 2021 Mar 15. Epub 2021 Mar 15.

Laboratoire d'Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Université Paris-Saclay, Orsay, France.

Gliomas are highly dynamic and heterogeneous tumours of the central nervous system (CNS). They constitute the most common neoplasm of the CNS and the second most common cause of death from intracranial disease after stroke. The advances in detailing the genetic profile of paediatric and adult gliomas along with the progress in MRI and PET multimodal molecular imaging technologies have greatly improved prognostic stratification of patients with glioma and informed on treatment decisions. Amino acid PET has already gained broad clinical application in the study of gliomas. PET imaging targeting the translocator protein (TSPO) has recently been applied to decipher the heterogeneity and dynamics of the tumour microenvironment (TME) and its various cellular components especially in view of targeted immune therapies with the goal to delineate pro- and anti-glioma immune cell modulation. The current review provides a comprehensive overview on the historical developments of TSPO PET for gliomas and summarizes the most relevant experimental and clinical data with regard to the assessment and quantification of various cellular components with the TME of gliomas by in vivo TSPO PET imaging.
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http://dx.doi.org/10.1007/s00259-021-05276-5DOI Listing
March 2021

Concomitant neurodegenerative pathologies contribute to the transition from mild cognitive impairment to dementia.

Alzheimers Dement 2021 Mar 4. Epub 2021 Mar 4.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Introduction: The aged brain frequently exhibits multiple pathologies, rather than a single hallmark pathology (pure pathology [PurP]), ranging from low/intermediate levels of additional pathology (LowP) to mixed severe pathology (mixed SevP). We investigated the frequency of PurP, LowP, and mixed SevP, and the impact of additional LowP on cognition.

Methods: Data came from 670 cases from the Brains for Dementia research program. Cases were categorized into PurP, mixed SevP, or a main disease with additional LowP; 508 cases had a clinical dementia rating.

Results: 69.9% of cases had LowP, 22.7% had PurP, and 7.5% had mixed SevP. Additional LowP increased the likelihood of having mild dementia versus mild cognitive impairment (MCI) by almost 20-fold (odds ratio = 19.5).

Discussion: Most aged individuals have multiple brain pathologies. The presence of one additional LowP can significantly worsen cognitive decline, increasing the risk of transitioning from MCI to dementia 20-fold. Multimorbidity should be considered in dementia research and clinical studies.
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http://dx.doi.org/10.1002/alz.12291DOI Listing
March 2021

Influence of APOE genotype in primary age-related tauopathy.

Acta Neuropathol Commun 2020 12 7;8(1):215. Epub 2020 Dec 7.

Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Salford Royal Hospital, The University of Manchester, Salford, M6 8HD, UK.

The term "Primary age-related tauopathy" (PART) was coined in 2014 to describe the common neuropathological observation of neurofibrillary tangles without associated beta-amyloid (Aβ) pathology. It is possible for PART pathology to be present in both cognitively normal and cognitively impaired individuals. Genetically, Apolipoprotein E (APOE) ε4 has been shown to occur less commonly in PART than in Alzheimer's disease (AD). Here, we investigate the relationships between PART, AD and those pathologically normal for age, with an emphasis on APOE and cognition, using 152 selected participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age and the Manchester arm of the Brains for Dementia Research cohort. APOE genotype differed between PART and AD with APOE ε2 more common in the former and APOE ε4 more common in the latter. Individuals with definite PART were less likely to be cognitively impaired than those with AD and those with pathology considered pathologically normal for age. We postulate that the lack of Aβ in definite PART cases may be due either to an increased frequency of APOE ε2 or decreased frequency of APOE ε4 as their resulting protein isoforms have differing binding properties in relation to Aβ. Similarly, an increased frequency of APOE ε2 or decreased frequency of APOE ε4 may lead to decreased levels of cognitive impairment, which raises questions regarding the impact of Aβ pathology on overall cognition in elderly subjects. We suggest that it may be possible to use the increased frequency of APOE ε2 in definite PART to assist neuropathological diagnosis.
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http://dx.doi.org/10.1186/s40478-020-01095-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720601PMC
December 2020

The spatial phenotype of genotypically distinct meningiomas demonstrate potential implications of the embryology of the meninges.

Oncogene 2021 Feb 1;40(5):875-884. Epub 2020 Dec 1.

Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre (MAHSC), St Mary's Hospital, School of Biological Sciences, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK.

Meningiomas are the most common primary brain tumor and their incidence and prevalence is increasing. This review summarizes current evidence regarding the embryogenesis of the human meninges in the context of meningioma pathogenesis and anatomical distribution. Though not mutually exclusive, chromosomal instability and pathogenic variants affecting the long arm of chromosome 22 (22q) result in meningiomas in neural-crest cell-derived meninges, while variants affecting Hedgehog signaling, PI3K signaling, TRAF7, KLF4, and POLR2A result in meningiomas in the mesodermal-derived meninges of the midline and paramedian anterior, central, and ventral posterior skull base. Current evidence regarding the common pathways for genetic pathogenesis and the anatomical distribution of meningiomas is presented alongside existing understanding of the embryological origins for the meninges prior to proposing next steps for this work.
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http://dx.doi.org/10.1038/s41388-020-01568-6DOI Listing
February 2021

Patterns of Mitochondrial TSPO Binding in Cerebral Small Vessel Disease: An PET Study With Neuropathological Comparison.

Front Neurol 2020 16;11:541377. Epub 2020 Oct 16.

Department of Neuroimaging, Institute of Psychiatry Psychology & Neuroscience, King's College London, London, United Kingdom.

Small vessel disease (SVD) is associated with cognitive impairment in older age and be implicated in vascular dementia. Post-mortem studies show proliferation of activated microglia in the affected white matter. However, the role of inflammation in SVD pathogenesis is incompletely understood and better biomarkers are needed. We hypothesized that expression of the 18 kDa translocator protein (TSPO), a marker of microglial activation, would be higher in SVD. Positron emission tomography (PET) was performed with the second-generation TSPO ligand [C]PBR28 in 11 participants with SVD. TSPO binding was evaluated by a two-tissue compartment model, with and without a vascular binding component, in white matter hyperintensities (WMH) and normal-appearing white matter (NAWM). In post-mortem tissue, in a separate cohort of individuals with SVD, immunohistochemistry was performed for TSPO and a pan-microglial marker Iba1. Kinetic modeling showed reduced tracer volume and blood volume fraction in WMH compared with NAWM, but a significant increase in vascular binding. Vascular [C]PBR28 binding was also increased compared with normal-appearing white matter of healthy participants free of SVD. Immunohistochemistry showed a diffuse increase in microglial staining (with Iba1) in sampled tissue in SVD compared with control samples, but with only a subset of microglia staining positively for TSPO. Intense TSPO staining was observed in the vicinity of damaged small blood vessels, which included perivascular macrophages. The results suggest an altered phenotype of activated microglia, with reduced TSPO expression, in the areas of greatest white matter ischemia in SVD, with implications for the interpretation of TSPO PET studies in older individuals or those with vascular risk factors.
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http://dx.doi.org/10.3389/fneur.2020.541377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596201PMC
October 2020

Mid to late-life scores of depression in the cognitively healthy are associated with cognitive status and Alzheimer's disease pathology at death.

Int J Geriatr Psychiatry 2021 05 20;36(5):713-721. Epub 2020 Nov 20.

Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK.

Objectives: Early diagnosis of Alzheimer's disease (AD) is essential for early interventions. Symptoms of depression could represent a prodromal stage of AD. Very early mood alterations may help to stratify those at highest risk of late-life AD. We aim to investigate associations between baseline/longitudinal scores for depression, presence of cognitive impairment and/or AD pathology at death.

Methods/design: Between 1991 and 2015, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent 10 waves of assessment using the Geriatric Depression Scale (GDS). AD pathology at death was evaluated in 106 eligible cases. Analyses aimed to examine associations between GDS scores, cognitive status and AD pathology (as measured by Braak stage, Thal phase and CERAD).

Results: Baseline GDS scores were significantly higher for those cognitively impaired at death than those cognitively normal. Significantly higher baseline GDS scores were found for those with greater Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores than those with lower CERAD scores. Similarly, significantly higher baseline GDS scores were found for those with a greater Braak stage than those with lower tau burden. These correlations remained after controlling for age at death, education and APOE ε4, but were less robust. Mean longitudinal GDS scores associated with cognition but not pathology.

Conclusions: GDS scores collected approximately 20 years before death were associated with cognitive status and AD pathology at death. We postulate that early AD-related pathological change produces raised GDS scores due to an overlapping neural basis with depression, and that this may be considered as an early diagnostic marker for AD.
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http://dx.doi.org/10.1002/gps.5470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048934PMC
May 2021

Effects of Alterations of Post-Mortem Delay and Other Tissue-Collection Variables on Metabolite Levels in Human and Rat Brain.

Metabolites 2020 Oct 29;10(11). Epub 2020 Oct 29.

Centre for Advanced Discovery & Experimental Therapeutics, Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M19 9NT, UK.

The use of post-mortem human tissue is indispensable in studies investigating alterations in metabolite levels in neurodegenerative conditions such as Alzheimer's disease (AD). However, variability between samples may have unknown effects on metabolite concentrations. The aim of this study was to characterize the impact of such variables. Cingulate gyrus was obtained from AD cases and controls, from three brain banks. Gas chromatography-mass spectrometry (GC-MS) was used to measure and compare the levels of 66 identifiable metabolites in these tissues to determine effects of tissue-collection variables. The effect of PMD was further investigated by analysis of rat brain cortex and cerebellum collected following post-mortem delays (PMDs) of zero to 72 h. Metabolite levels between cases and controls were not replicable across cohorts with variable age- and gender-matching, PMD, and control Braak staging. Analysis of rat tissues found significant effects of PMD on 31 of 63 identified metabolites over periods up to 72 h. PMD must be kept under 24 h for metabolomics analyses on brain tissues to yield replicable results. Tissues should also be well age- and gender-matched, and Braak stage in controls should be kept to a minimum in order to minimize the impact of these variables in influencing metabolite variability.
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http://dx.doi.org/10.3390/metabo10110438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694048PMC
October 2020

A Gadolinium Metal-Organic Framework Film as a Converter Layer for Neutron Detection.

Chempluschem 2020 Oct;85(10):2349-2356

Departamento de Física de la Materia Condensada, Instituto de Nanociencia y Nanotecnología, Centro Atómico Constituyentes, Comisión Nacional de Energía Atómica (CNEA), Avenida General Paz 1499, 1650, San Martín, Buenos Aires, Argentina.

Metal-organic frameworks (MOFs) are known for their versatility in terms of their crystalline structure, porosity, resistance to temperature, radiation damage, and luminescence among others. Gadolinium (Gd) is one of the elements with the highest reported cross-section for low energy neutron capture, producing internal conversion electrons and γ rays as a result of the neutron absorption. The development of Gd-BTC films (BTC=1,3,5-benzenetricarboxylate) is shown that were deposited on Si and Al substrates by airbrushing, and characterized by profilometry, Raman, EDX and X-ray diffraction. Radiation damage, thermal decomposition and neutron absorption of these films were studied as well. Gd-BTC films were attached to CMOS devices (Complementary Metal-Oxide-Semiconductor), which are sensible to the internal conversion electrons, in order to build a neutron detector. The devices Gd-BTC/CMOS could selectively detect neutrons in the presence of γ rays with a thermal neutron detection efficiency of 3.3±0.1 %, a signal to noise ratio of 6 : 1, and were suitable to obtain images.
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http://dx.doi.org/10.1002/cplu.202000586DOI Listing
October 2020

3D DESI-MS lipid imaging in a xenograft model of glioblastoma: a proof of principle.

Sci Rep 2020 10 5;10(1):16512. Epub 2020 Oct 5.

Wolfson Molecular Imaging Centre, Division of Informatics, Imaging and Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M20 3LJ, UK.

Desorption electrospray ionisation mass spectrometry (DESI-MS) can image hundreds of molecules in a 2D tissue section, making it an ideal tool for mapping tumour heterogeneity. Tumour lipid metabolism has gained increasing attention over the past decade; and here, lipid heterogeneity has been visualised in a glioblastoma xenograft tumour using 3D DESI-MS imaging. The use of an automatic slide loader automates 3D imaging for high sample-throughput. Glioblastomas are highly aggressive primary brain tumours, which display heterogeneous characteristics and are resistant to chemotherapy and radiotherapy. It is therefore important to understand biochemical contributions to their heterogeneity, which may be contributing to treatment resistance. Adjacent sections to those used for DESI-MS imaging were used for H&E staining and immunofluorescence to identify different histological regions, and areas of hypoxia. Comparing DESI-MS imaging with biological staining allowed association of different lipid species with hypoxic and viable tissue within the tumour, and hence mapping of molecularly different tumour regions in 3D space. This work highlights that lipids are playing an important role in the heterogeneity of this xenograft tumour model, and DESI-MS imaging can be used for lipid 3D imaging in an automated fashion to reveal heterogeneity, which is not apparent in H&E stains alone.
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http://dx.doi.org/10.1038/s41598-020-73518-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536442PMC
October 2020

Author Correction: YAP1/TAZ drives ependymoma-like tumour formation in mice.

Nat Commun 2020 Sep 28;11(1):4934. Epub 2020 Sep 28.

Kinases and Brain Development Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-18851-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522079PMC
September 2020

Clinical outcomes in an adult patient with mannose phosphate isomerase-congenital disorder of glycosylation who discontinued mannose therapy.

Mol Genet Metab Rep 2020 Dec 7;25:100646. Epub 2020 Sep 7.

Adult Inherited Metabolic Diseases, Salford Royal NHS Foundation Trust, Salford M6 8HD, United Kingdom.

The mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) is caused by phosphomannose isomerase deficiency. Clinical features include hyperinsulinaemic hypoglycaemia, protein losing enteropathy, hepatomegaly and hepatic fibrosis, digestive symptoms and coagulation abnormalities. The condition is treated with mannose supplementation. Long-term outcomes in adults are not well described. We present a case of an adult female patient who discontinued mannose therapy in her adolescence. In adulthood she developed gastrointestinal problems, chronic anaemia and osteophytes in her knees.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490551PMC
December 2020

Colorectal carcinoma to pituitary tumour: tumour to tumour metastasis.

Br J Neurosurg 2020 Sep 21:1-4. Epub 2020 Sep 21.

Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

We document a patient with colon adenocarcinoma who presented with rapidly worsening visual impairment. Staging computer tomography and subsequent magnetic resonance scans documented a sellar, suprasellar lesion compressing the optic chiasm. The patient underwent trans-sphenoidal surgery to relieve optic chiasm compression and obtain tissue for diagnosis. Histological examination revealed a metastatic mucinous adenocarcinoma in a gonadotroph pituitary neuroendocrine tumour (PitNET, formerly pituitary adenoma). The patient underwent adjuvant radiotherapy to the sella and chemotherapy but he died nine months after pituitary surgery. This report highlights the diagnostic and management challenges of metastases to PitNET.
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http://dx.doi.org/10.1080/02688697.2020.1823937DOI Listing
September 2020

Primary glomus tumour of the pituitary gland: diagnostic challenges of a rare and potentially aggressive neoplasm.

Virchows Arch 2021 May 12;478(5):977-984. Epub 2020 Sep 12.

Department of Neurosurgery, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

Primary non-neuroendocrine tumours of the pituitary gland and sella are rare lesions often challenging to diagnose. We describe two cases of clinically aggressive primary glomus tumour of the pituitary gland. The lesions occurred in a 63-year-old male and a 30-year-old female who presented with headache, blurred vision and hypopituitarism. Neuroimaging demonstrated large sellar and suprasellar tumours invading the surrounding structures. Histologically, the lesions were characterised by angiocentric sheets and nests of atypical cells that expressed vimentin, smooth muscle actin and CD34. Perivascular deposition of collagen IV was also a feature. Case 2 expressed synaptophysin. INI-1 (SMARCB1) expression was preserved. Both lesions were mitotically active and demonstrated a Ki-67 labelling index of 30%. Next-generation sequencing performed in case 1 showed no mutations in the reading frame of 37 commonly mutated oncogenes, including BRAF and KRAS. Four pituitary glomus tumours have previously been reported, none of which showed features of malignant glomus tumour. Similar to our two patients, three previous examples displayed aggressive behaviour.
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http://dx.doi.org/10.1007/s00428-020-02923-4DOI Listing
May 2021

Influence of Genotype on Mortality and Cognitive Impairment.

J Alzheimers Dis Rep 2020 Jul 23;4(1):281-286. Epub 2020 Jul 23.

Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK.

While many studies have examined the associations between genotype and mortality, findings have often been conflicting and it remains unclear whether genotype affects longevity. Using selected individuals from the Manchester arm of the Brains for Dementia Research programme and University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, we investigated relationships between genotype and age at death in both cognitively normal and cognitively impaired individuals. Results indicated that carrying the 4 allele led to a reduced chance in an individual reaching 80+ years and remaining cognitively healthy. Conversely, 2 carriers tended to live longer and remain cognitively normal. These findings add to the evidence that genotype influences longevity, especially in cognitively impaired individuals who carry the 4 allele.
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http://dx.doi.org/10.3233/ADR-200203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458549PMC
July 2020

Neuropathology of a case of fragile X-associated tremor ataxia syndrome without tremor.

Neuropathology 2020 Dec 23;40(6):611-619. Epub 2020 Aug 23.

Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Neuroscience & Experimental Psychology, The University of Manchester, Salford Royal Hospital, Salford, UK.

Fragile X-associated tremor ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG trinucleotide expansion from 55 to 200 repeats in the non-coding region of the fragile X mental retardation 1 (FMR1) gene (FMR1). Clinical features include cognitive decline, progressive tremor, and gait ataxia. Neuropathologically, FXTAS shows white matter changes, hippocampal and cerebellar involvement, and p62-positive eosinophilic intranuclear inclusions in astrocytes and neurons. Here, we document the neuropathological findings from a subject who developed cognitive impairment but not tremor and was proved to have genetically confirmed FMR1 premutation. Microscopically, typical p62-postive intranuclear inclusions were present in all the regions examined. Neocortical regions demonstrated gliosis of layer I and mild degree of neuronal loss and atrophy across the other layers. The molecular, Purkinje's cell, and granule cell layers of the cerebellar folia demonstrated mild gliosis, and cerebellar white matter was mildly affected. Aside from p62-positive inclusions, the hippocampus was spared. Arteries in the deep white matter often showed changes consistent with moderate small vessel disease (SVD). Reactive gliosis and severe SVD were features of basal ganglia. Florid reactive astrocytosis was found in the white matter of all regions. Axonal loss and features of axonal damage were found in the white matter of the centrum semiovale. Microglial activation was widespread and evenly seen in both the white matter and grey matter, although the grey matter appeared more severely affected. Pathology associated with Alzheimer's disease was limited. Similarly, no abnormal accumulations of α-synuclein were present. We postulate that age at death and disease duration may play a role in the extent of the pathological features associated with FXTAS. The present results suggest that immunohistochemical staining for p62 can help with the diagnosis of cases with atypical phenotype. In addition, it is likely that the cognitive impairment observed was a result of white matter changes.
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http://dx.doi.org/10.1111/neup.12674DOI Listing
December 2020

The Contribution of Vascular Pathology Toward Cognitive Impairment in Older Individuals with Intermediate Braak Stage Tau Pathology.

J Alzheimers Dis 2020 ;77(3):1005-1015

Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK.

Background: The pathological features of Alzheimer's disease (AD) are well described but little is known as to how both neurodegeneration and vascular changes might interact in causing cognitive impairment.

Objective: The present study aims to investigate relationships between vascular and AD pathology in cognitively healthy and cognitively impaired individuals with a particular emphasis on those at intermediate Braak tau stages.

Methods: We investigated the interplay between Braak tau stage and measures of vascular pathology as described by the vascular cognitive impairment neuropathology guidelines (VCING) in 185 brains from the Brains for Dementia Research programme and The University of Manchester Longitudinal Study of Cognition in Healthy Old Age. VCING asserts that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, and moderate/severe arteriosclerosis in occipital white matter accurately predicts the contribution of cerebrovascular pathology to cognitive impairment.

Results: We found that the extent of arteriosclerosis in the occipital white matter did not differ between cognitive groups at intermediate (III-IV) Braak stages whereas moderate/severe leptomeningeal occipital cerebral amyloid angiopathy was greater in cognitively impaired than normal individuals at Braak stage III-IV. This finding remained significant after controlling for effects of age, sex, CERAD score, Thal phase, presence/severity of primary age-related tauopathy, presence/severity of limbic-predominant age-related TDP43 encephalopathy and small vessel disease in basal ganglia.

Conclusion: Interventions targeting cerebral amyloid angiopathy may contribute to delay the onset of cognitive impairment in individuals with intermediate Alzheimer's type pathology.
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http://dx.doi.org/10.3233/JAD-200339DOI Listing
January 2020

Mechanisms of Mitochondrial Dysfunction in Lysosomal Storage Disorders: A Review.

J Clin Med 2020 Aug 11;9(8). Epub 2020 Aug 11.

School of Pharmacy, Liverpool John Moore University, Byrom Street, Liverpool L3 3AF, UK.

Mitochondrial dysfunction is emerging as an important contributory factor to the pathophysiology of lysosomal storage disorders (LSDs). The cause of mitochondrial dysfunction in LSDs appears to be multifactorial, although impaired mitophagy and oxidative stress appear to be common inhibitory mechanisms shared amongst these heterogeneous disorders. Once impaired, dysfunctional mitochondria may impact upon the function of the lysosome by the generation of reactive oxygen species as well as depriving the lysosome of ATP which is required by the V-ATPase proton pump to maintain the acidity of the lumen. Given the reported evidence of mitochondrial dysfunction in LSDs together with the important symbiotic relationship between these two organelles, therapeutic strategies targeting both lysosome and mitochondrial dysfunction may be an important consideration in the treatment of LSDs. In this review we examine the putative mechanisms that may be responsible for mitochondrial dysfunction in reported LSDs which will be supplemented with morphological and clinical information.
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http://dx.doi.org/10.3390/jcm9082596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463786PMC
August 2020

The inflammatory microenvironment in vestibular schwannoma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa023. Epub 2020 Feb 27.

Manchester Centre for Clinical Neurosciences, Salford Royal Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

Vestibular schwannomas are tumors arising from the vestibulocochlear nerve at the cerebellopontine angle. Their proximity to eloquent brainstem structures means that the pathology itself and the treatment thereof can be associated with significant morbidity. The vast majority of these tumors are sporadic, with the remainder arising as a result of the genetic syndrome Neurofibromatosis Type 2 or, more rarely, related schwannomatosis. The natural history of these tumors is extremely variable, with some tumors not displaying any evidence of growth, others demonstrating early, persistent growth and a small number growing following an extended period of indolence. Emerging evidence now suggests that far from representing Schwann cell proliferation only, the tumor microenvironment is complex, with inflammation proposed to play a key role in their growth. In this review, we provide an overview of this new evidence, including the role played by immune cell infiltration, the underlying molecular pathways involved, and biomarkers for detecting this inflammation in vivo. Given the limitations of current treatments, there is a pressing need for novel therapies to aid in the management of this condition, and we conclude by proposing areas for future research that could lead to the development of therapies targeted toward inflammation in vestibular schwannoma.
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http://dx.doi.org/10.1093/noajnl/vdaa023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212860PMC
February 2020

The microenvironment in sporadic and neurofibromatosis type II-related vestibular schwannoma: the same tumor or different? A comparative imaging and neuropathology study.

J Neurosurg 2020 May 29:1-11. Epub 2020 May 29.

1Department of Neurosurgery, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre.

Objective: Inflammation and angiogenesis may play a role in the growth of sporadic and neurofibromatosis type 2 (NF2)-related vestibular schwannoma (VS). The similarities in microvascular and inflammatory microenvironment have not been investigated. The authors sought to compare the tumor microenvironment (TME) in sporadic and NF2-related VSs using a combined imaging and tissue analysis approach.

Methods: Diffusion MRI and high-temporal-resolution dynamic contrast-enhanced (DCE) MRI data sets were prospectively acquired in 20 NF2-related and 24 size-matched sporadic VSs. Diffusion metrics (mean diffusivity, fractional anisotropy) and DCE-MRI-derived microvascular biomarkers (transfer constant [Ktrans], fractional plasma volume, tissue extravascular-extracellular space [ve], longitudinal relaxation rate, tumoral blood flow) were compared across both VS groups, and regression analysis was used to evaluate the effect of tumor size, pretreatment tumor growth rate, and tumor NF2 status (sporadic vs NF2-related) on each imaging parameter. Tissues from 17 imaged sporadic VSs and a separate cohort of 12 NF2-related VSs were examined with immunohistochemistry markers for vessels (CD31), vessel permeability (fibrinogen), and macrophage density (Iba1). The expression of vascular endothelial growth factor (VEGF) and VEGF receptor 1 was evaluated using immunohistochemistry, Western blotting, and double immunofluorescence.

Results: Imaging data demonstrated that DCE-MRI-derived microvascular characteristics were similar in sporadic and NF2-related VSs. Ktrans (p < 0.001), ve (p ≤ 0.004), and tumoral free water content (p ≤ 0.003) increased with increasing tumor size and pretreatment tumor growth rate. Regression analysis demonstrated that with the exception of mean diffusivity (p < 0.001), NF2 status had no statistically significant effect on any of the imaging parameters or the observed relationship between the imaging parameters and tumor size (p > 0.05). Tissue analysis confirmed the imaging metrics among resected sporadic VSs and demonstrated that across all VSs studied, there was a close association between vascularity and Iba1+ macrophage density (r = 0.55, p = 0.002). VEGF was expressed by Iba1+ macrophages.

Conclusions: The authors present the first in vivo comparative study of microvascular and inflammatory characteristics in sporadic and NF2-related VSs. The imaging and tissue analysis results indicate that inflammation is a key contributor to TME and should be viewed as a therapeutic target in both VS groups.
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http://dx.doi.org/10.3171/2020.3.JNS193230DOI Listing
May 2020

YAP1/TAZ drives ependymoma-like tumour formation in mice.

Nat Commun 2020 05 13;11(1):2380. Epub 2020 May 13.

Kinases and Brain Development Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.

YAP1 gene fusions have been observed in a subset of paediatric ependymomas. Here we show that, ectopic expression of active nuclear YAP1 (nlsYAP5SA) in ventricular zone neural progenitor cells using conditionally-induced NEX/NeuroD6-Cre is sufficient to drive brain tumour formation in mice. Neuronal differentiation is inhibited in the hippocampus. Deletion of YAP1's negative regulators LATS1 and LATS2 kinases in NEX-Cre lineage in double conditional knockout mice also generates similar tumours, which are rescued by deletion of YAP1 and its paralog TAZ. YAP1/TAZ-induced mouse tumours display molecular and ultrastructural characteristics of human ependymoma. RNA sequencing and quantitative proteomics of mouse tumours demonstrate similarities to YAP1-fusion induced supratentorial ependymoma. Finally, we find that transcriptional cofactor HOPX is upregulated in mouse models and in human YAP1-fusion induced ependymoma, supporting their similarity. Our results show that uncontrolled YAP1/TAZ activity in neuronal precursor cells leads to ependymoma-like tumours in mice.
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http://dx.doi.org/10.1038/s41467-020-16167-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220953PMC
May 2020

Evidence that levels of nine essential metals in post-mortem human-Alzheimer's-brain and ex vivo rat-brain tissues are unaffected by differences in post-mortem delay, age, disease staging, and brain bank location.

Metallomics 2020 06;12(6):952-962

Centre for Advanced Discovery & Experimental Therapeutics, Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester M19 9NT, UK. and School of Biological Sciences, Faculty of Science, University of Auckland, Private Bag 92 019, Auckland 1142, New Zealand.

Studies of neurodegenerative conditions such as Alzheimer's disease (AD) using post mortem brain tissues have uncovered several perturbations in metals such as copper, iron, and zinc. However, studies of the effects of key, potentially confounding variables on these tissues are currently lacking. Moreover, human-brain tissues have limited availability, further enhancing the difficulty of matching potentially-significant variables including age, sex-matching, post-mortem delay (PMD), and neuropathological stage. This study aimed to investigate the effects of such factors and how they might influence metal concentrations in post-mortem brains. Cingulate gyrus from AD cases and matched controls was obtained from two brain banks, based in Auckland, New Zealand and Manchester, UK. Inductively-coupled plasma mass spectrometry (ICP-MS) was employed to measure levels of nine essential metals in brain tissues, and compared concentrations between cases and controls, and between cohorts, to analyse effects of age, sex, Braak stage, brain weight, and PMD. The same methods were used to investigate the effects of PMD under more controlled conditions using ex vivo healthy adult rat-brain tissue. Metal concentrations in human brain were found to be unmodified by differences in age, sex-matching, Braak stage, brain weight, and PMD between cohorts. Some metals were, however, found to vary significantly across different regions in rat brains. These results indicate that investigations of metal homeostasis in AD and other neurodegenerative conditions can be reliably performed using brain tissues without confounding by varying PMD, age, sex-matching, brain weight, and Braak stage. However, regions of study should be selected carefully.
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http://dx.doi.org/10.1039/d0mt00048eDOI Listing
June 2020

B cell rich meningeal inflammation associates with increased spinal cord pathology in multiple sclerosis.

Brain Pathol 2020 07 26;30(4):779-793. Epub 2020 Apr 26.

Department of Brain Sciences, Faculty of Medicine, Imperial College, London, UK.

Increased inflammation in the cerebral meninges is associated with extensive subpial cortical grey matter pathology in the forebrain and a more severe disease course in a substantial proportion of secondary progressive multiple sclerosis (SPMS) cases. It is not known whether this relationship extends to spinal cord pathology. We assessed the contribution of meningeal and parenchymal immune infiltrates to spinal cord pathology in SPMS cases characterized in the presence (F+) or absence (F-) of lymphoid-like structures in the forebrain meninges. Transverse cryosections of cervical, thoracic and lumbar cord of 22 SPMS and five control cases were analyzed for CD20+ B cells, CD4+ and CD8+ T cells, microglia/macrophages (IBA-1+), demyelination (myelin oligodendrocyte glycoprotein+) and axon density (neurofilament-H+). Lymphoid-like structures containing follicular dendritic cell networks and dividing B cells were seen in the spinal meninges of 3 out of 11 F+ SPMS cases. CD4+ and CD20+ cell counts were increased in F+ SPMS compared to F- SPMS and controls, whilst axon loss was greatest in motor and sensory tracts of the F+ SPMS cases (P < 0.01). The density of CD20+ B cells of the spinal leptomeninges correlated with CD4+ T cells and total B and T cells of the meninges; with the density of white matter perivascular CD20+ and CD4+ lymphocytes (P < 0.05); with white matter lesion area (P < 0.05); and the extent of axon loss (P < 0.05) in F+ SPMS cases only. We show that the presence of lymphoid-like structures in the forebrain is associated with a profound spinal cord pathology and local B cell rich meningeal inflammation associates with the extent of cord pathology. Our work supports a principal role for B cells in sustaining inflammation and tissue injury throughout the CNS in the progressive disease stage.
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http://dx.doi.org/10.1111/bpa.12841DOI Listing
July 2020

How to Classify the Pituitary Neuroendocrine Tumors (PitNET)s in 2020.

Cancers (Basel) 2020 02 22;12(2). Epub 2020 Feb 22.

Pathological Department, Foch Hospital, 40 rue Worth Suresnes 92151, France.

Adenohypophyseal tumors, which were recently renamed pituitary neuroendocrine tumors (PitNET), are mostly benign, but may present various behaviors: invasive, "aggressive" and malignant with metastases. They are classified into seven morphofunctional types and three lineages: lactotroph, somatotroph and thyrotroph (PIT1 lineage), corticotroph (TPIT lineage) or gonadotroph (SF1 lineage), null cell or immunonegative tumor and plurihormonal tumors. The WHO 2017 classification suggested that subtypes, such as male lactotroph, silent corticotroph and Crooke cell, sparsely granulated somatotroph, and silent plurihormonal PIT1 positive tumors, should be considered as "high risk" tumors. However, the prognostic impact of these subtypes and of each morphologic type remains controversial. In contrast, the French five-tiered classification, taking into account the invasion, the immuno-histochemical (IHC) type, and the proliferative markers (Ki-67 index, mitotic count, p53 positivity), has a prognostic value validated by statistical analysis in 4 independent cohorts. A standardized report for the diagnosis of pituitary tumors, integrating all these parameters, has been proposed by the European Pituitary Pathology Group (EPPG). In 2020, the pituitary pathologist must be considered as a member of the multidisciplinary pituitary team. The pathological diagnosis may help the clinician to adapt the post-operative management, including appropriate follow-up and early recognition and treatment of potentially aggressive forms.
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http://dx.doi.org/10.3390/cancers12020514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072139PMC
February 2020

Primary epithelial-myoepithelial carcinoma of the pituitary gland.

Neuropathology 2020 Jun 3;40(3):261-267. Epub 2020 Jan 3.

Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Primary salivary gland-like tumors of the sella are rare and often challenging to diagnose. They reportedly derive from serous and mucinous glands that remain trapped in the infundibulum during embryogenesis. We report a 68-year-old man who presented with partial left third cranial nerve palsy, visual loss in the left eye without visual field defects, headache, weight loss and reduced muscle bulk. Neuroimaging studies demonstrated a solid and cystic, avidly enhancing lesion expanding the pituitary fossa and extending to the left cavernous sinus. The patient underwent craniotomy and the tissue removed showed features of epithelial-myoepithelial carcinoma similar to the salivary gland, skin and breast counterpart. No primary tumor was found outside the sella. The lesion behaved aggressively despite radio-chemotherapy and the patient died 22 months from the onset. The tumor showed a novel TP53 in-frame deletion (Gly154del) while no variants were found in H-RAS hotspot regions (codons 12, 13 and 61). Our report expands the spectrum of salivary gland-like tumors primarily occurring in the sella and emphasizes the need for specialist review of rare, non-neuroendocrine tumors of the pituitary and sella regions.
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http://dx.doi.org/10.1111/neup.12628DOI Listing
June 2020

Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome.

JAMA Neurol 2020 03;77(3):377-387

Department of Neuroscience, Brighton and Sussex Medical School, Brighton, United Kingdom.

Importance: Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes but have not been prospectively studied.

Objective: To define the distinguishing features of PSP and CBS subtypes and to assess their usefulness in facilitating early diagnosis and separation from PD.

Design, Setting, Participants: This cohort study recruited patients with APS and PD from movement disorder clinics across the United Kingdom from September 1, 2015, through December 1, 2018. Patients with APS were stratified into the following groups: those with Richardson syndrome (PSP-RS), PSP-subcortical (including PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (including PSP-frontal and PSP-CBS overlap subtypes), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer disease (CBS-AD), and CBS-non-AD. Data were analyzed from February 1, through May 1, 2019.

Main Outcomes And Measures: Baseline group comparisons used (1) clinical trajectory; (2) cognitive screening scales; (3) serum neurofilament light chain (NF-L) levels; (4) TRIM11, ApoE, and MAPT genotypes; and (5) volumetric magnetic resonance imaging measures.

Results: A total of 222 patients with APS (101 with PSP, 55 with MSA, 40 with CBS, and 26 indeterminate) were recruited (129 [58.1%] male; mean [SD] age at recruitment, 68.3 [8.7] years). Age-matched control participants (n = 76) and patients with PD (n = 1967) were included for comparison. Concordance between the antemortem clinical and pathologic diagnoses was achieved in 12 of 13 patients with PSP and CBS (92.3%) undergoing postmortem evaluation. Applying the Movement Disorder Society PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP from 58 to 101. Forty-nine of 101 patients with reclassified PSP (48.5%) did not have the classic PSP-RS subtype. Patients in the PSP-subcortical group had a longer diagnostic latency and a more benign clinical trajectory than those in PSP-RS and PSP-cortical groups. The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures (area under the curve [AUC], 0.84-0.89), cognitive profile (AUC, 0.80-0.83), serum NF-L level (AUC, 0.75-0.83), and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups. Eight of 17 patients with CBS (47.1%) undergoing cerebrospinal fluid analysis were identified as having the CBS-AD subtype. Patients in the CBS-AD group had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment, and higher APOE-ε4 allele frequency than those in the CBS-non-AD group (AUC, 0.80-0.87; P < .05). Serum NF-L levels distinguished PD from all PSP and CBS cases combined (AUC, 0.80; P < .05).

Conclusions And Relevance: These findings suggest that studies focusing on the PSP-RS subtype are likely to miss a large number of patients with underlying PSP tau pathology. Analysis of cerebrospinal fluid defined a distinct CBS-AD subtype. The PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis.
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http://dx.doi.org/10.1001/jamaneurol.2019.4347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990759PMC
March 2020

Imaging and Tissue Biomarkers of Choline Metabolism in Diffuse Adult Glioma: 18F-Fluoromethylcholine PET/CT, Magnetic Resonance Spectroscopy, and Choline Kinase α.

Cancers (Basel) 2019 Dec 7;11(12). Epub 2019 Dec 7.

Department of Brain Sciences, Imperial College London, London SW7 2AZ, UK.

The cellular and molecular basis of choline uptake on PET imaging and MRS-visible choline-containing compounds is not well understood. Choline kinase alpha (ChoKα) is an enzyme that phosphorylates choline, an essential step in membrane synthesis. We investigate choline metabolism through 18F-fluoromethylcholine (18F-FMC) PET, MRS, and tissue ChoKα in human glioma. Fourteen patients with a suspected diffuse glioma underwent multimodal 3T MRI and dynamic 18F-FMC PET/CT prior to surgery. Co-registered PET and MRI data were used to target biopsies to regions of high and low choline signal, and immunohistochemistry for ChoKα expression was performed. The 18F-FMC/PET differentiated WHO (World Health Organization) grade IV from grade II and III tumours, whereas MRS differentiated grade III/IV from grade II tumours. Tumoural 18F-FMC/PET uptake was higher than in normal-appearing white matter across all grades and markedly elevated within regions of contrast enhancement. The 18F-FMC/PET correlated weakly with MRS Cho ratios. ChoKα expression on IHC was negative or weak in all but one glioblastoma sample, and did not correlate with tumour grade or imaging choline markers. MRS and 18F-FMC/PET provide complimentary information on glioma choline metabolism. Tracer uptake is, however, potentially confounded by blood-brain barrier permeability. ChoKα overexpression does not appear to be a common feature in diffuse glioma.
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http://dx.doi.org/10.3390/cancers11121969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966628PMC
December 2019