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.
A Histologic Study of the Circadian System in Parkinson Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy
De Pablo-Fernández E, Courtney R, Warner TT, Holton JL
Importance: Circadian dysfunction may be associated with the symptoms and neurodegeneration in Parkinson disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP), although the underlying neuroanatomical site of disruption and pathophysiological mechanisms are not fully understood.
Objective: To perform a neuropathological analysis of disease-specific inclusions in the key structures of the circadian system in patients with PD, MSA, and PSP.
Figure Legend: Immunohistochemical Staining of Representative Sections of the Suprachiasmatic Nucleus (SCN) and Pineal GlandA, Immunohistochemistry for vasointestinal peptide was used for identification of the SCN (A, arrowhead). The inset shows expression in neuronal cell bodies and processes. B and C, Immunohistochemical staining of the SCN for α-synuclein (B) showing Lewy pathology in a patient with Parkinson disease and for phosphorylated tau (C) showing tau pathology in a patient with progressive supranuclear palsy. D, Immunohistochemical staining of pineal gland tissue for α-synuclein showing Lewy pathology in a patient with Parkinson disease. Scale bar in D represents 520 μm in A and 25 μm in the inset of A and in B through D. PVN indicates paraventricular nucleus; SON, supraoptic nucleus; and 3V, third ventricle.
Conclusions and Relevance: Disease-related neuropathological changes were found in the SCN but not in the pineal gland in PD and PSP, while both structures were preserved in MSA, reflecting different pathophysiological mechanisms that may have important therapeutic implications.
Pedro Melo Barbosa,Talyta Grippe, Andrew J Lees, Sean O’Sullivan,Atbin Djamshidian,Thomas T Warner
Introduction: Previous research estimates the lifetime prevalence of compulsive sexual behaviour (CSB) in individuals with Parkinson’s disease (PD) to be 2.7%. CSB has also been associated with male gender and earlier onset of PD. Although both dopamine agonists (DAs) and, to a lesser extent, levodopa have been associated with impulsive compulsive behaviours (ICBs),it is still unclear whether higher levodopa doses are a risk factor for the development of CSB in patients with PD.
Methods: Patients with ICBs were identified from a database of individuals with PD and ICBs who were seen at the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK, and who had participated in three previous research projects over an 8-year period (from 2008 to 2016). All the ICB cases were recruited to research studies from PD clinics at the National Hospital and selected due to the reporting of ICBs. All cases underwent a thorough clinical investigation as well as a detailed semistructured interview conducted by one of the authors. Hospital notes were reviewed by a movement disorder specialist (PMB) for clinical and demographic data. Levodopa equivalent daily dose (LEDD) was calculated according to previously published guidelines.3 Data were analysed using the software SPSS V.24.
Results: In total, 111 patients with PD and ICBs were included, 55 with CSB (CSB+), 56 without CSB (CSB-). CSB was the most frequent ICB identified in our cohort. Eighty-six were males, mean age at the time of ICBs was 56.9 years and mean PD duration at onset of ICBs was 11.3 years. Average age of PD onset was 46.3 years. Only 9 patients were not exposed to dopamine agonists. The proportion of males was higher in the CSB group (CSB- 60.7%; CSB+ 94.5%; p <0.001) and they developed ICBs at younger age (CSB- 59.16 years; CSB+ 54.62; p = 0.02). The CSB+ group was using a higher dose of dopaminergic treatment and levodopa as measured by total L-dopa equivalent daily dose (CSB- 1163.6; CSB+ 1400.15; p = 0.014) and levodopa daily dose (CSB- 704.93; CSB+ 994.51; p = 0.043). Dopamine agonist use was similar between groups.
Conclusion: The data from this study suggest that CSB is more frequent in males and tends to appear earlier than other ICBs. CSB may be the most frequent ICB associated with PD. Furthermore, patients with CSB are more likely to develop multiple ICBs. When compared to other types of ICBs, this behavioural addiction appears to be driven by higher levodopa doses. Data from larger studies are needed to confirm these novel findings.
Objective: To investigate the association between type 2 diabetes mellitus (T2DM) and subsequent Parkinson disease (PD).
Methods: Linked English national Hospital Episode Statistics and mortality data (1999-2011) were used to conduct a retrospective cohort study. A cohort of individuals admitted for hospital care with a coded diagnosis of T2DM was constructed, and compared to a reference cohort. Subsequent PD risk was estimated using Cox regression models. Individuals with a coded diagnosis of cerebrovascular disease, vascular parkinsonism, drug-induced parkinsonism, and normal pressure hydrocephalus were excluded from the analysis.
Results: A total of 2,017,115 individuals entered the T2DM cohort and 6,173,208 entered the reference cohort. There were significantly elevated rates of PD following T2DM (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.29-1.35; p < 0.001). The relative increase was greater in those with complicated T2DM (HR 1.49, 95% CI 1.42-1.56) and when comparing younger individuals (HR 3.81, 95% CI 2.84-5.11 in age group 25-44 years).
Conclusions: We report an increased rate of subsequent PD following T2DM in this large cohort study. These findings may reflect shared genetic predisposition and/or disrupted shared pathogenic pathways with potential clinical and therapeutic implications.