The Phenomenology, Pathophysiology and Progression of the Core Features of Lewy Body Dementia

Lewy body dementias – Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) - are disabling neurodegenerative conditions defined pathologically by the presence of intraneuronal α-synuclein rich aggregates (‘Lewy bodies’ and ‘Lewy neurites’). These disorders are characterized by a set of ‘core’ clinical features, namely cognitive fluctuations, visual hallucinations, motor parkinsonism, and most recently added, REM sleep behaviour disorder. These features are central to the diagnosis of Lewy bodies dementias (especially DLB) and discriminate them from other neurodegenerative disorders. Despite decades of research, the etiopathogenesis underlying Lewy body disorders is poorly understood. This accounts for the relative lack of objective biomarkers and both symptomatic and disease modifying therapies. The present thesis comprises a series of investigations that seeks to understand the phenomenology, pathophysiology, and clinical progression of Lewy body dementias through focus on each of the core clinical features. Systematic review and empiric studies are organized under the respective headings of cognitive fluctuations, visual hallucinations, REM sleep behaviour disorder, motor features, interrelationships, and clinical progression of the core features. Novel clinical and pathophysiological insights are obtained which have implications for the prediction and diagnosis of core features, the development of new objective biomarkers, and clinical endpoints of disease progression. From these studies, a shared pathophysiological basis for the core features is postulated and potential avenues for future directions are highlighted, focusing on replication and validation of new biomarkers and clinical measures, discovery of new biomarkers and mechanisms, and translation to prodromal and patient cohorts

Crosstalk between Depression, Anxiety, and Dementia: Comorbidity in Behavioral Neurology and Neuropsychiatry

This Special Issue highlights the most recent research on depression, anxiety and dementia, with attention to comorbidity in a range of diseases. The symptoms of depression, anxiety and dementia are the most common comorbid manifestations present in patients suffering from neurodegenerative and psychiatric diseases. Together, these illnesses constitute an extremely complex and challenging research field due to their inherent multifactorial causative factors, heterogeneous pathogenesis, and mental and behavioral manifestations. This Special Issue covers laboratory, clinical and statistical studies on the crosstalk between depression, anxiety, dementia, Alzheimer’s disease, multiple sclerosis, schizophrenia, diabetes mellitus, Down’s syndrome, and/or compulsive disorders. It contains contributions from 71 authors, has been reviewed by 25 referees, and edited by three academic editors and one managing editor

Fluctuations of attention network activation during the resting state reflect fluctuations in subjective attentional state.

peer reviewe

Molecular mechanisms underlying cerebral small vessel disease associated with mutations in COL4A1

Cerebral small vessel diseases (cSVDs) are the leading cause of stroke and vascular dementia, but the underlying pathogenic mechanisms are unknown. Humans and mice with autosomal dominant mutations in the collagen-encoding gene COL4A1 present with brain pathology that typifies cSVD. Data in this thesis reveals divergent pathogenic mechanisms in two Col4a1 mutant mouse models and offers viable therapeutic strategies for treating related cSVDs. Col4a1G1344D cSVD was associated with the loss of myogenic tone due to blunted pressure-induced smooth muscle cell (SMC) depolarization. Dysregulation of membrane potential was linked to impaired Ca2+-dependent activation of transient receptor potential melastatin 4 (TRPM4) channels caused by disruption in sarcoplasmic reticulum (SR) Ca2+ signaling. Deficits were prevented by treating mice with 4-phenylbutyrate, a compound that promotes the trafficking of misfolded proteins from the SR, suggesting accumulation of mutant collagen in the SR contributes to the pathogenesis. The fundamental defect in Col4a1G394V cSVD was the depletion of phosphatidylinositol 4,5 bisphosphate (PIP2), a necessary cofactor for TRPM4 and inwardly-rectifying K+ (KIR) channels, in vascular SMCs and endothelial cells. This caused a loss of myogenic tone and neurovascular coupling contributing to cSVD. PIP2 depletion was linked to increased phosphoinositide 3-kinase (PI3K) activity acting downstream of transforming growth factor-beta (TGF-β) receptors. Restoring PIP2 by blocking PI3K or TGF-β receptors restored myogenic tone, neurovascular coupling, and memory function. Differences in pathogenic mechanisms between mutations within the same gene highlight the diverse causes and the need for specific treatments of cSVDs

25th Annual Computational Neuroscience Meeting: CNS-2016

Abstracts of the 25th Annual Computational Neuroscience Meeting: CNS-2016 Seogwipo City, Jeju-do, South Korea. 2–7 July 201

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong