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UCL Queen Square Institute of Neurology

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Research

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

Fig.1: Macroscopic and microscopic CTE pathology. Mild global cerebral atrophy with enlargement of the lateral ventricle can be seen
(A1, B1), along with prominent atrophy of the hippocampus (B1), and severe pallor and neuronal loss in the substantia nigra (C1, arrows;
C3). Widespread phosphorylated tau (AT8, MN1020, 1:600; Invitrogen) pathology is seen in the frontal cortex (A2, A3), consisting of thornshaped
astrocytes, pre-tangles, tangles and threads. Astrocytic tau pathology shows some emphasis in the depths of the cortical sulci
(A2, red arrowheads), where thorn-shaped astrocytes can be seen in a perivascular distribution (A4). Neuronal tau pathology shows
emphasis in superficial neocortical laminae at the crests of the gyri (A5, blue arrowheads). Subpial thorn-shaped astrocytes are seen in
the neocortex (A3, black arrows, superior frontal gyrus), midbrain (C2, black arrows and C4) and pons (not shown). Thorn-shaped
astrocytes are also present in the subependymal white matter adjacent to the lateral (B2) and fourth (D3) ventricles. In the hippocampus
(B3), a dense meshwork of threads, tangles and pre-tangles (yellow arrowheads) are evident in the CA2 region (B4), with pre-tangles seen
in the dentate gyrus (B6) and in the CA4 region where proximal dendritic swellings can also be seen (B5, green arrowheads). Occasional
TDP43 (2E2-D3, H00023435-M01, 1:500; Abnova) immunoreactive neuronal cytoplasmic inclusions are seen in the dentate gyrus (B7,
purple arrowhead). Occasional tangle, pre-tangle and thread pathology can also be seen in the substantia nigra (C5) and dentate nucleus
(D2). There was widespread amyloid-β pathology corresponding to Thal phase 5, but no α-synuclein pathology was present (not shown).
Scale bar: 5.5 mm in A2, 700 μm in A3, 170 μm in A4, 85 μm in A5, 1.4 mm in B2, 2 mm in B3, 250 μm in B4, 120 μm in B5, 140 μm in B6,
50 μm in B7, 8 mm in C2, 500 μm in C3, 110 μm in C4, 160 μm in C5, 250 μm in D2 and 140 μm in D3.

 

 

 

 


 

 

 

 

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

"Neurology" 2023

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

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

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)

 

 
 
May 2024