Current Research Highlights

Head of Queen Square Brain Bank  Professor Thomas Warner

Clinical Associate Professor and Honorary Consultant Neuropathologist Dr Zane Jaunmuktane

Clinical Associate Professor and Honorary Consultant Neuropathologist Dr Karl Frontzek

“QSBB is an invaluable resource for clinicians and scientists worldwide. For 30 years we have built a unique collection of tissue focussing on neurodegenerative diseases. Our own research programme, and that of groups to whom we have supplied tissue for research, has resulted in a greater understanding of the underlying processes that lead to the death of specific brain cells, improvements in diagnostic precision, and opened new avenues for more effective treatments.”

Pathology of neurodegenerative disease for the general neurologist

Patrick W Cullinane, Sarah Wrigley, Jacy Bezerra Parmera , Fernanda Valerio, Thomas O Millner, Karen Shaw, Eduardo De Pablo-Fernandez, Thomas T Warner, Zane Jaunmuktane

"Pract Neurol 2024"

Abstract: Neurodegeneration refers to progressive dysfunction or loss of selectively vulnerable neurones from brain and spinal cord regions. Despite important advances in fluid and imaging biomarkers, the definitive diagnosis of most neurodegenerative diseases still relies on neuropathological examination. Not only has careful clinicopathological correlation shaped current clinical diagnostic criteria and informed our understanding of the natural history of neurodegenerative diseases, but it has also identified conditions with important public health implications, including variant Creutzfeldt-Jakob disease, iatrogenic amyloid-β and chronic traumatic encephalopathy. Neuropathological examination may also point to previously unsuspected genetic diagnoses with potential implications for living relatives. Moreover, detailed neuropathological assessment is crucial for research studies that rely on curated postmortem tissue to investigate the molecular mechanisms responsible for neurodegeneration and for biomarker discovery and validation. This review aims to elucidate the hallmark pathological features of neurodegenerative diseases commonly seen in general neurology clinics, such as Alzheimer's disease and Parkinson's disease; rare but well-known diseases, including progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy and more recently described entities such as chronic traumatic encephalopathy and age-related tau astrogliopathy.

Introduction: Most adult-onset neurodegenerative diseases are considered proteinopathies because they are characterised by misfolding of native peptides and proteins such as amyloid-β (Aβ) peptide, tau, α-synuclein, transactive DNA-binding protein 43 (TDP43) and prion proteins, which then assemble into larger filaments before aggregating to form morphologically distinct cellular inclusions or extracellular parenchymal plaques (). More than 50 diseases are associated with misfolded protein pathology including well-established clinicopathological conditions such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), as well as more recently identified neuropathological entities of uncertain clinical significance such as age-related tau astrogliopathy (ARTAG) and limbic-predominant age-related TDP43 encephalopathy (LATE). In most neurodegenerative diseases there is topographical spreading of misfolded protein pathology between synaptically-connected brain regions with different conformations of the same misfolded protein generally leading to specific patterns of regional and cellular vulnerability. Pathology may also develop in situ because of cell autonomous factors such as high metabolic demand and genetic risk factors (including possible somatic mutations) that render some neurones more susceptible to protein misfolding. Whatever the mechanism, the clinical features are generally determined by the anatomical distribution of neuropathology, meaning that similar clinical phenotypes may result from several different proteinopathies. Due to this phenotypic overlap, the accurate diagnosis of many neurodegenerative diseases in life is challenging and neuropathology remains the gold standard for diagnosis. Consequently, systematic brain banking and clinicopathological correlation have been the cornerstone of clinical diagnostic criteria for all the major neurodegenerative diseases.21figure 1

Conclusions: Neuropathological examination not only remains the gold standard for reaching a definitive diagnosis in most neurodegenerative diseases, but it can also have important implications for living relatives as well as wider public health implications. New pathological entities requiring further clinicopathological correlation continue to be described and with advances in molecular biology techniques, neuropathological examination of tissue from well-established conditions such as AD and PD remains as important as ever to facilitate high quality research into the molecular mechanisms of these diseases and for the discovery and validation of tissue biomarkers..

Neuropathologic Validation and Diagnostic Accuracy of Presynaptic Dopaminergic Imaging in the Diagnosis of Parkinsonism

Alexandra Hastings, Patrick Cullinane, Srah Wrigley, Tamas Revesz, Huw R. Morris, John C. Dickson, Zane Jaunmuktane, Thomas T. Warner, Eduardo De Pablo-Fernandez 

"Neurology" 2024

Abstract

Background and objectives: Degeneration of the presynaptic nigrostriatal dopaminergic system is one of the main biological features of Parkinson disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), which can be measured using single-photon emission CT imaging for diagnostic purposes. Despite its widespread use in clinical practice and research, the diagnostic properties of presynaptic nigrostriatal dopaminergic (DAT) imaging in parkinsonism have never been evaluated against the diagnostic gold standard of neuropathology. The aim of this study was to evaluate the diagnostic parameters of DAT imaging compared with pathologic diagnosis in patients with parkinsonism.

Methods: Retrospective cohort study of patients with DAT imaging for the investigation of a clinically uncertain parkinsonism with brain donation between 2010 and 2021 to the Queen Square Brain Bank (London). Patients with DAT imaging for investigation of pure ataxia or dementia syndromes without parkinsonism were excluded. Those with a pathologic diagnosis of PD, MSA, PSP, or CBD were considered presynaptic dopaminergic parkinsonism, and other pathologies were considered postsynaptic for the analysis. DAT imaging was performed in routine clinical practice and visually classified by hospital nuclear medicine specialists as normal or abnormal. The results were correlated with neuropathologic diagnosis to calculate diagnostic accuracy parameters for the diagnosis of presynaptic dopaminergic parkinsonism.

Results: A total of 189 patients (109 men [57.7%]; median [IQR] age at death of 72.3 [66.7–79.0] years) were included. A summary of the demographic and clinical data for the total cohort and by neuropathologic diagnosis is presented in Table 1. There were 47 patients with PD, 42 patients with MSA, 73 patients with PSP, and 10 patients with CBD. The PDP- group comprised 17 patients with several pathologic diagnoses including 8 with frontotemporal lobar degeneration, 3 with Alzheimer disease, 3 without an identifiable neurodegenerative pathology, 1 with prion disease, and 2 with restricted degenerative disorders involving the cerebellum and olivopallidal structures.

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