Assessment of the visual thalamic circuitry in hallucinations in dementia with Lewy bodies

PhD ThesisBackground Visual hallucinations occur in 70-90% of patients with dementia with Lewy bodies (DLB) and are related to decreased quality of life for patients. However, the underlying neuropathological changes that promote the manifestation of visual hallucinations in DLB are not known. Several hypotheses of visual hallucinations in DLB have either directly implicated the lateral geniculate nucleus (LGN), pulvinar and superior colliculus or suggested impairments in their putative functions. Methods Post-mortem LGN, pulvinar and superior colliculus tissue was obtained from DLB cases with a clinical history of visual hallucinations and compared to cognitively normal control and Alzheimer’s disease (AD) cases without visual hallucinations. Neuropathological lesions were quantified in individual cases using densitometry and neuronal and glial cell populations were quantified with stereology. RNA sequencing and subsequent bioinformatics analysis of biological pathway alterations was performed by a collaborator on pulvinar tissue from DLB and non-hallucinating control cases. The bioinformatics data was used to identify protein targets based on pathway alterations, which were then investigated using western blot analysis. Results Lewy body pathology and neuronal loss was specifically found in the pulvinar and superior colliculus of DLB cases, particularly in regions implicated in visual attention and target selection. In contrast, AD cases had more widespread degenerative changes. Molecular analysis of the pulvinar demonstrated reduced expression of several synaptic markers, concomitant with elevated expression of several astrocytic markers in DLB. Conclusion ii The relative specificity of changes in visual thalamic regions may contribute to the occurrence of visual hallucinations in DLB. Synaptic degeneration in the pulvinar likely further impedes visual attentional function in DLB. The present results may indicate DLB patients have impairments in directing visual attention to external stimuli, thus facilitating visual hallucinations by an over-reliance upon expectations and experience rather than stimulus-driven perception.Yvonne Emily Mairy, whose generous donation to the National Institute for Health Research Biomedical Research Unit in Lewy body dementia at Newcastle University funded this project. I a

The Trial of Queen Caroline and the Impeachment of President Clinton: Law As a Weapon for Political Reform

This Article addresses the trial of Queen Caroline in the English House of Lords in 1820, and the impeachment in 1998 and trial in 1999 of President Clinton

Neurodegenerative brain changes are associated with area deprivation in the United Kingdom: findings from the Brains for Dementia Research study

Socioeconomic disadvantage is associated with greater risk of dementia. This has been theorised to reflect inequalities in cognitive reserve, healthcare access, lifestyle, and other health factors which may contribute to the clinical manifestation of dementia. We aimed to assess whether area deprivation in the United Kingdom was associated with greater risk or severity of the specific neurodegenerative diseases which lead to dementia in a multi-centre cohort with autopsy assessment. Participants underwent clinical assessment prior to brain tissue donation post-mortem. Each then underwent detailed, standardised neuropathological assessment. National area deprivation statistics were derived for each participant’s neighbourhood, for use as a predictor in binary and ordinal logistic models assessing the respective presence and severity of staging of key neuropathological changes, adjusting for theorised confounders. Individuals from among the 20% most deprived neighbourhoods in the United Kingdom had significantly higher neurofibrillary tangle and neuritic plaque staging, and increased risk of cerebral amyloid angiopathy. These findings were not explained by a greater risk of diabetes or hypertension, APOE genotype, alcohol misuse or tobacco smoking, sex, or age differences. A sensitivity analysis conditioning on baseline cognitive impairment did not meaningfully change the observed association. Socioeconomic disadvantage may contribute to dementia incidence through a greater severity of specific neuropathological changes (neurofibrillary tangles, neuritic plaques, and cerebral amyloid angiopathy), independent of other indirect influences. Mechanisms through which deprivation is associated with these require further exploration

Extravascular fibrinogen in the white matter of Alzheimer's disease and normal aged brains : implications for fibrinogen as a biomarker for Alzheimer's disease

The research was supported by the Alzheimer’s Society (grant numbers AS-PG-2013-011 and AS-JF-18-01). Tissue for this study was provided by the Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council (G0400074) and by Brains for Dementia research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK.The blood‐brain barrier (BBB) regulates cerebrovascular permeability and leakage of blood‐derived fibrinogen has been associated with cerebral arteriolosclerosis small vessel disease (SVD) and subsequent white matter lesions (WML). Furthermore, BBB‐dysfunction is associated with the pathogenesis of Alzheimer's disease (AD) with the presence of CSF plasma proteins suggested to be a potential biomarker of AD. We aimed to determine if extravascular fibrinogen in the white matter was associated with the development of AD hallmark pathologies, i.e., hyperphosphorylated tau (HPτ) and amyloid‐β (Aβ), SVD, cerebral amyloid angiopathy (CAA) and measures of white matter damage. Using human post‐mortem brains, parietal tissue from 20 AD and 22 non‐demented controls was quantitatively assessed for HPτ, Aβ, white matter damage severity, axonal density, demyelination and the burden of extravascular fibrinogen in both WML and normal appearing white matter (NAWM). SVD severity was determined by calculating sclerotic indices. WML‐ and NAWM fibrinogen burden was not significantly different between AD and controls nor was it associated with the burden of HPτ or Aβ pathology, or any measures of white matter damage. Increasing severity of SVD was associated with and a predictor (both p < 0.05) of both higher WML‐ and NAWM fibrinogen burden (both P<0.05) in controls only. In cases with minimal SVD NAWM fibrinogen burden was significantly higher in the AD cases (p<0.05). BBB dysfunction was present in both non‐demented and AD brains and was not associated with the burden of AD‐associated cortical pathologies. BBB dysfunction was strongly associated with SVD but only in the non‐demented controls. In cases with minimal SVD, BBB dysfunction was significantly worse in AD cases possibly indicating the influence of CAA. In conclusions, extravascular fibrinogen is not associated with AD hallmark pathologies but indicates SVD, suggesting that the presence of fibrinogen in the CSF is not a surrogate marker for AD pathology.PostprintPeer reviewe

Prion-like α-synuclein pathology in the brain of infants with Krabbe disease

Krabbe disease is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene that causes accumulation of the toxic sphingolipid psychosine. GALC variants are also associated with Lewy body diseases, an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in Krabbe disease has pathological similarities to that in Lewy body disease, we performed an observational post-mortem study of Krabbe disease brain tissue (n = 4) compared to infant controls (n = 4) and identified widespread accumulations of α-synuclein. To determine whether α-synuclein in Krabbe disease brain displayed disease-associated pathogenic properties we evaluated its seeding capacity using the real-time quaking-induced conversion assay in two cases for which frozen tissue was available and strikingly identified aggregation into fibrils similar to those observed in Lewy body disease, confirming the prion-like capacity of Krabbe disease-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it results from alterations to biological pathways, such as sphingolipid metabolism. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in Lewy body disease

Babylonian encounters in the Upper Diyala River Valley:Contextualizing the results of regional survey and the 2016–2017 excavations at Khani Masi

Kassite Babylonia counts among the great powers of the Late Bronze Age Near East. Its kings exchanged diplomatic letters with the pharaohs of Egypt and held their own against their Assyrian and Elamite neighbors. Babylonia's internal workings, however, remain understood in their outlines only, as do its elite's expansionary ambitions, the degrees to which they may have been realized, and the nature of ensuing imperial encounters. This is especially the case for the region to the northeast, where the Mesopotamian lowlands meet the Zagros piedmonts in the Diyala River valley and where a series of corridors of movement intersect to form a strategic highland-lowland borderland. In this paper, we present critical new results of regional survey in the Upper Diyala plains of northeast Iraq and excavations at the Late Bronze Age site of Khani Masi. Not only do our data and analyses expand considerably the known extent of Babylonia's cultural sphere, but also the monumental character of Khani Masi and its wider settlement context prompt a fundamental rethinking of the nature and chronology of Babylonian presence in this transitional landscape. As such, this paper contributes an important new case study to the field of archaeological empire and borderland studies