Third Scientific Session - Neurodegeneration II

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder associated with neuroglial accumulation of 4-repeat tau protein. Kovacs et al. have recently proposed a new staging system to categorise the severity of PSP pathology, using the distribution of tau-aggregates as they progress from subcortical to cerebellar and cortical regions. Here, we test the new PSP pathology staging system in an independent series of PSP, and test the potential association between pathology stage and clinical severity at death. We include tissue from 35 people with a clinical diagnosis of PSP. Donors had attended longitudinal clinical studies at the Cambridge Centre for Parkinson-plus including assessment of clinical severity by the PSP rating scale (PSPRS) and cognitive performance by the revised Addenbrooke’s Cognitive Examination (ACE-R). We rated tau pathology from none-to-severe in six regions. We focused on (I) astrocytic tau inclusions in striatum, frontal and occipital regions, and (II) neuronal and oligodendroglia tau inclusions in globus pallidus, subthalamic nucleus, and cerebellum. Thirty-two cases (91%) readily conformed to the new staging system, ranging from stage 2 to 6 and across clinical phenotypes of PSP. Neuropathology stages correlated with clinical severity at death using both PSPRS and ACE-R, weighted for the interval between last assessment and donation. Our study supports the proposed sequential distribution of tau-aggregates in PSP pathology, and the hypothesised relationship between clinical and neuropathological severity. For future studies, in order to standardise rating between centres, we propose a set of operational criteria for region-specific thresholds of tau burden, and a visual guide.

Introduction: Lewy body dementia (LBD) is characterised by transient clinical features, such as fluctuating cognition and visual hallucinations. Fast-spiking interneurons regulate the firing of ensembles of cortical neurons and their dysfunction induces changes to cortical activity that can manifest as transient changes in attention or visual perception. As mitochondrial dysfunction has been reported in LBD, and fast-spiking interneurons are highly reliant on efficient production of energy by mitochondria, we hypothesised that fast-spiking interneurons would be degenerated in LBD and that this would relate to cognitive symptoms.

Methods: Post-mortem prefrontal and inferior temporal cortex tissue was obtained from 12 control and 12 LBD cases for stereological analysis of pyramidal and interneuron number, histopathological analysis of neuropathological lesions, and immunofluorescent analysis of the mitochondrial respiratory chain.

Results: LBD cases had fewer fast-spiking interneurons in prefrontal and temporal cortices, whilst no difference was observed in pyramidal neurons despite their vulnerability to Lewy body formation. Immunofluorescence suggested lower levels of Complex I of the mitochondrial respiratory chain in both interneurons and pyramidal neurons in LBD. In prefrontal cortex, fewer interneurons and low levels of Complex I were both significantly correlated with the antemortem severity and frequency of cognitive fluctuations.

Discussion: These findings suggest dysfunction of fast-spiking interneurons may contribute to transient cognitive features of LBD. Due to the higher energy demands of interneurons, we speculate that Complex I deficiency has a greater impact on their function and survival than pyramidal neurons and are currently employing organotypic cultures of cortical neurons to investigate this further.

Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD) are clinical diagnoses based on the 1 year rule and the presentation of an array of different symptoms. Dopaminergic, serotonergic, cholinergic and noradrenergic neurotransmitter deficits have been reported in both conditions. However, further research is required to determine possible differences in brainstem pathology that might underlie the different clinical presentations. For example, the serotonergic pathway originates from the dorsal raphe nucleus (DRN) in the rostral pons, projecting across the entire brain to regulate a wide range of physiological functions, such as appetite, vomiting, body temperature, sleep-wake cycle, as well as emotional state and cognition, specifically learning and memory. In this study, we have examined the serotonergic projections from the DRN to the frontal cortex in a cohort of patients with DLB, PDD or PD without dementia. Immunohistochemical and image analysis techniques have been performed using a neuronal marker, tryptophan hydroxylase-2 (TPH2), to enable a comparison between neuronal quantity in each of the clinical subgroups. Hence, the serotonergic pathway may be implicated in the pathogenesis of LBDs and potentially correlate with cognitive fluctuations and dysfunctions in emotional state. 

Introduction: Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by a variable combination of parkinsonism, ataxia and autonomic failure. Similar to Parkinson’s disease (PD), MSA is an α-synucleinopathy, but its pathological hallmark consists of glial cytoplasmic inclusions (GCIs) containing α-synuclein in oligodendrocytes. We previously identified consistent changes in MOBP and HIP1 DNA methylation status in MSA as well as downregulation of MOBP mRNA. Here, we investigated MOBP and HIP1 protein levels and localization in MSA and other neurodegenerative diseases. 

Methods: Using western blotting, immunohistochemistry and proximity ligation assays, we investigated protein levels and localization in brain tissue from MSA, PD, progressive supranuclear palsy (PSP), Huntington’s disease, and healthy controls. 

Results: Although MOBP and HIP1 protein levels were not significantly different between MSA and controls, we found striking differences between MSA and the other neurodegenerative diseases. Interestingly, in a mildly affected brain region (occipital lobe) in MSA, which should represent an earlier stage of the disease pathogenesis, but not in a severely affect region (cerebellum), MOBP and HIP1 protein levels correlate with MSA disease duration. Additionally, we found that MOBP and HIP1 are mislocalized into the GCIs in MSA, where they interact with α-synuclein. Only HIP1 occasionally mislocalizes into the characteristic proteinaceous inclusions in PSP (e.g. coiled bodies), but not in the other diseases. 

Conclusions: This work identified MOBP and HIP1 as new constituents of GCIs and emphasizes the relevance of these two loci to the pathogenesis of MSA.