Topic: dementia with Lewy bodies

Synapse degeneration contributes to cognitive decline in neurodegenerative diseases. We have previously demonstrated synaptic accumulation of pathological alpha-synuclein in synapses in brain tissue from people who died with Dementia with Lewy Bodies (DLB), but whether this occurs in Parkinson’s disease (PD), a related neurodegenerative synucleinopathy, remains unknown, as do mechanisms of synapse degeneration in these diseases. Oligomeric tau has been implicated in synaptotoxicity in tauopathies, including Alzheimer’s disease, and growing evidence supports that the co-aggregation of different

Neurodegenerative disorders have a substantial immune component, implicating both peripheral and central immune systems. Despite neuroinflammation being linked to greater dementia risk, the interaction of central and peripheral inflammatory processes to influence disease courses remain ill-understood. A key site-of-interest for this interaction is the choroid plexus. Beyond secreting cerebrospinal fluid (CSF), it has been proposed as a gateway for peripheral immune cell entry into the central nervous system (CNS). As such, increases in choroid volume measurable with structural magnetic resonan

Preclinical research into dementia with Lewy bodies (DLB) is challenging due to the lack of α-synucleinopathy animal models that do not also develop Parkinsonism. To address this issue, we have developed a new mouse model for investigating the impact of α-synuclein (α-Syn) overexpression and aggregation on driving cortical and hippocampal circuit dysfunction. Using bilateral stereotaxic injections of adeno-associated virus (AAVs) vectors, we transduced overexpression of human SNCA (encoding α-Syn) with mScarlet (red fluorophore), or an mScarlet-only control vector. We targeted either dorsal hi

Prodromal network hyperexcitability and mitochondrial dysfunction underly the pathogenesis of various forms of dementia. However, the role of hippocampal hyperexcitability and mitochondria in prodromal dementia with Lewy bodies (DLB) is unclear.We conducted multi-electrode array (MEA) recordings to investigate early hippocampal activity in a transgenic mouse model of DLB which harbours an alanine to proline point mutation (A30P) in the alpha synuclein gene (SNCA), causing overexpression. Hippocampal slices from young pre-symptomatic (2-4 months) male A30P (N = 6 slices/4 mice) and wild-type (W

There is growing evidence that patients with dementia with Lewy bodies exhibit early cortical network excitability and neuroinflammatory changes. To explore the link between the two we have used a transgenic mouse that expresses human mutant alpha-synuclein (hA30P). The study investigated whether there were early pre-symptomatic, neuroinflammatory changes in hA30P mice that could contribute to the network hyperexcitability previously observed.Studies were conducted using 1 month and 2-4 months old hA30P mice of both sexes and compared to age-matched wild-type (WT) mice. Fixed, frozen hippocamp

Blood biomarkers are becoming increasingly important for clinical trial stratification and healthcare. Therefore this work explored these existing markers’ diagnostic accuracy and ability to differentially diagnose Dementia with Lewy Bodies (DLB) from Alzheimer’s Disease (AD). A multi-modal, combinatorial approach was taken to validate plasma and PET imaging markers’ utilities.The singular and combined ability of two emerging phospho-tau markers, p-tau217 and p-tau231, to differentiate DLB from AD was tested in a well-characterised cohort of patients over the age of 50. Following from this, pl

Dementia with Lewy Bodies (DLB) is caused by aggregation of insoluble α-synuclein (α-syn) in neurons and patients exhibit cognitive impairment involving the anterior cingulate cortex (ACC). Parvalbumin-expressing interneurons (PVIs) are critical for normal cognitive function and are often surrounded by a specialised extracellular matrix, the perineuronal nets (PNNs). Loss of PVIs and PNNs occurs in Alzheimer’s disease but their role in DLB remains unclear. In addition, neuroinflammatory changes may also play an early role in DLB. Using transgenic mice expressing human mutant α-syn (hA30P), we

Aims: α-synuclein is a protein that is highly expressed in brain neurons. Its normal function is still unknown, but it is thought to be crucial to the onset of dementia with Lewy bodies (DLB). As of now, DLB cannot be sufficiently explained by mutations in the α-synuclein protein because there are so few α-synuclein mutations found in DLB. Nevertheless, several studies have revealed that individuals with DLB also co-exhibit Aβ accumulation in the brain, suggesting that Aβ could be involved in α-synuclein neurotoxicity. However, the exact molecular mechanism behind Aβ-induced α-synuclein toxici

Synucleinopathies (e.g. Parkinson's disease and dementia with Lewy bodies) are neurodegenerative conditions characterized by an accumulation of alpha-synuclein from the prodromal phase. Yet, the pathophysiology is far from being completely understood. We have recently identified the cortical synaptic depletion of eukaryotic elongation factor 1A proteins (EEF1A) at early stages of the disease in a mouse model of synucleinopathy (human alpha-synuclein expressing animals under PDGF promoter specific to various brain tissues, PDGF-hSyn).In order to link EEF1A proteins to synucleinopathy changes, w

The kinase-ligase pair PINK1-PRKN recognizes and selectively labels worn-out and dysfunctional mitochondria with phosphorylated ubiquitin (pS65-Ub) to facilitate their elimination via autophagy (mitophagy). Although typically transient, pS65-Ub serves as a quantitative marker of mitochondrial damage but can also remain elevated due to insufficient degradation and flux through lysosomes. In human autopsy brain, the number of pS65-Ub positive cells increases with age but is also independently associated with Lewy body (LB), neurofibrillary tangles (NFT), and senile plaque (SP) burden. However, p

FPVS is an electroencephalography marker of discrimination between two classes of frequency tagged stimuli (standards and oddballs). The technique can detect neurodegeneration-related impairment in recognition memory without active response or task comprehension. Here, we develop FPVS as a probe of low-level visual function, with a view to its future use as a sensitive diagnostic marker of visuospatial cognitive impairment. Thirty subjects (21 (±5) years, 7 males) completed five FPVS conditions that implicitly measured their ability to discriminate an oddball line orientation (1°,5°,10°,30°,80