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Alzheimer’s and Parkinson’s diseases (AD and PD) are the commonest degenerative neurological disorders of old age.
There are many rarer disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and beta-propellor protein associated degeneration (BPAN) that variably share clinical and pathological features.
Research to date has uncovered three crucial processes within the cell that are major contributors to malfunction and cell loss. These include clustering of individual cellular proteins to form insoluble aggregates, dysfunction of mitochondria, the energy generators within the cell, and autophagy, the cellular process to eliminate damaged components including the defective mitochondria and large protein aggregates.
Cell biology of neurodegeneration
Our research primarily involves the study of cell models of neurodegeneration, developing “disease-in-a-dish” to study the cellular processes involved in nerve cell death.
Of particular importance is work with patient-derived skin cells that can be differentiated into relevant nerve cell types via induced pluripotent stem cells (iPSCs).
This gives the opportunity to study cell defects within the context of the patient’s own unique genetic background and interacting genetic risk factors that singly or collectively contribute to disease propensity.
Clinico-pathological studies of neurodegenerative disorders
Our clinical work focuses on movement disorders and dementias, including PSP, CBD, BPAN that present at the National Hospital of Neurology and Neurosurgery (NHNN) at Queen Square. Being the largest neurology referral centre in the country, this gives the opportunity to investigate the more unusual presentations.
Current projects include looking at the neurobehavioural and cognitive complications of Parkinson’s disease. In collaboration with the Queen Square Brain Bank and our colleagues in the UCL Queen Square Institute of Neurology, we are able to carry out detailed neuropathological and genetic investigations of these disorders and have produced important papers describing the classification, staging and genetic correlates of these devastating disorders.
Recent Publications
Late Presentation of Chronic Traumatic Encephalopathy in a Former Association Football Player
Patrick W. Cullinane, Sarah Wrigley, Teisha Y. Bradshaw, Karen Shaw, Samuel Shribman, Eduardo de Pablo Fernandez, Thomas T. Warner, Zane Jaunmuktane
"Mov Dis Clin Pract" June 2023
Abstract
Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by widespread accumulation of hyperphosphorylated tau that typically occurs in people who have suffered repetitive head impacts. To date, very few cases have been reported in association football players. Objectives: To describe the clinicopathological features of a case of CTE in an 84-year-old former football
player who was clinically diagnosed as having dementia with Lewy bodies (DLB). Methods: A retrospective review of the patient’s primary care and hospital medical records was performed along with a comprehensive neuropathological examination. Results: This patient presented at age 84 with symmetrical parkinsonism and cognitive impairment that was exacerbated by prochlorperazine. His condition was rapidly progressive with recurrent falls within 1 year. Other features included headaches, depression, anxiety, suicidal ideation, disturbed sleep and aggression. He received a clinical diagnosis of DLB and died approximately 2 years after the onset of symptoms. A postmortem examination revealed stage 4 CTE. Conclusions: While the contemporaneous onset of parkinsonism and cognitive symptoms in the context of possible neuroleptic sensitivity is suggestive of DLB, the additional symptoms of aggressive behavior, depression and suicidality in a former football player are consistent with the neuropathological diagnosis of CTE. This case, which is notable for the late presentation, demonstrates that CTE may masquerade as other dementias and highlights the importance of seeking a history of repetitive head impacts.
 Fig.1: Macroscopic and microscopic CTE pathology. Mild global cerebral atrophy with enlargement of the lateral ventricle can be seen |
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Association Between Orthostatic Hypotension and Dementia in Patients With Parkinson Disease and
Multiple System Atrophy
Iñigo Ruiz Barrio, Yasuo Miki, Zane T. Jaunmuktane, Thomas Warner, Eduardo De Pablo-Fernandez
Abstract
Background and Objectives: Orthostatic hypotension (OH) increases dementia risk in patients with Parkinson disease (PD), although the underlying mechanisms and whether a similar association between OH and cognitive impairment exists in other synucleinopathies remain unknown. The aim is to evaluate the association between OH and dementia risk in patients with PD, and cognitive impairment risk in patients with multiple system atrophy (MSA), and to explore relevant clinical and neuropathologic factors to understand underlying pathogenic mechanisms.
Methods: This is a retrospective cohort study. Medical records throughout the entire disease course of consecutive patients with neuropathology-confirmed PD and MSA from the Queen Square
Brain Bank were systematically reviewed. Time of onset and severity of OH-related symptoms were documented, and their association with other clinical and neuropathologic variables was
evaluated. Dementia risk for patients with PD and cognitive impairment risk for patients with MSA were estimated using multivariable hazard regression.
Results: One hundred thirty-two patients with PD and 137 with MSA were included. Patients with MSA developed OH more frequently, earlier in the disease course and with more severe symptoms. Cumulative dementia prevalence was higher in patients with PD. Multivariable adjusted regression models showed that early OH, but not its symptom severity, increased dementia risk in patients with PD by 14% per year (hazard ratio [HR] = 0.86; 95% CI, 0.80-0.93) and cognitive impairment risk in patients with MSA by 41% per year (HR = 0.59; 95% CI, 0.42-0.83). Early OH was not associated with increased α-synuclein, β-amyloid, tau, Alzheimer, or cerebrovascular pathologies. No significant associations were found between severity of OH symptoms and other clinical or neuropathologic variables.
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 | Fig 1. Scatterplot Showing the Association Between Time of Onset of Orthostatic Hypotension and Time to Development of Cognitive Impairment for Cases With MSA (Orange) and Dementia for PD Cases (Blue) |
 | Fig 2. Kaplan-Meier of Cumulative Risk of Dementia in PD and Risk of Cognitive Impairment in MSA by Time of Onset of Orthostatic Hypotension (A) and (C) and Severity of Symptoms of Orthostatic Hypotension (B) and (D) |
Neuroendocrine abnormalities in Parkinson's disease.
De Pablo-Fernández E, Breen DP, Bouloux PM, Barker RA, Foltynie T, Warner TT.
Neuroendocrine abnormalities are common in Parkinson’s disease (PD) and include disruption of melatonin secretion, disturbances of glucose, insulin resistance and bone metabolism, and body weight changes. They have been associated with multiple non-motor symptoms in PD and have important clinical consequences. We discuss pathophysiological mechanisms, clinical implications, and pharmacological and non-pharmacological interventions based on the current evidence. We also review recent advances in the field, focusing on the potential targets for development of neuroprotective drugs in Parkinson’s disease and suggest future areas for research.
De Pablo-Fernandez E, Courtney R, Holton JL, Warner TT.
Mov Disord. 2016 Nov 28. doi: 10.1002/mds.26868. [Epub ahead of print]
Our study was the first in providing a correlation of the presence of Lewy pathology (alpha-synuclein deposition) in the hypothalamus with severity of non-motor symptoms in Parkinson’s disease. We showed that Lewy pathology deposition occurs at early stages (even pre-clinical phase) and progressively affects the supraoptic, paraventricular and infundibular nuclei of the hypotahalamus in patients with Parkinson’s disease. Lewy pathology in these hypothalamic nuclei does not correlate with the presence of certain non-motor symptoms and the dopaminergic hypothalamic system was not impaired. This suggests that dysfunction of other cell mechanisms not exclusively related to the classical neuropathological alterations might be impaired.
Neurodegeneration
Astrogliopathy predominates the earliest stage of corticobasal degeneration pathology.
Ling H, Kovacs G, Vonsattel JP, Davey K, Mok KY, Morris H, Warner T, Hardy J, Holton JL, Revesz T.
Brain (2016) 139 (12): 3237-3252.
Unlike in Alzheimer's disease (AD) and progressive supranuclear palsy (PSP), it is not clear where tau pathology originates or how it progresses. Dr Helen Ling at the RLWI and colleagues have identified that astrocytic plaques are more prominent than neuronal lesions in preclinical CBD cases when compared with end-stage CBD cases, suggesting CBD may begin as an astrogliopathy at a very early disease stage.