Is sectioning justifiable? The ethics of involuntary treatment.

Posted by Saturday, 8 March 2014 , , ,

Introduction
Depriving people with mental disorders of their liberty had been an unquestioned practise for centuries and even the 1845 Lunacy Act explicitly prohibited the discharge of patients deemed dangerous or unfit, together with removing their right to challenge their detention in court. Evermore, vesting the monopoly of coercion (and violence) to a legitimate authority is more or less nested within the foundations of our societies, justified by the aim of safeguarding justice, human rights and overall wellbeing. However, since 1845 many advances have occurred in the understanding and management of mental disorders, while the extent to which the state or other institutions should interfere with individuals’ freedom has been debated to different directions. The involuntary institutionalization and/or treatment of the mentally ill “who are a danger to themselves or to others,” although still common in most countries, has generated many heated discussions and hence aim of this essay is to discuss the ethical considerations intrinsic to such a proposition i.e. “it is the right thing to do,” and those related to its practical and legal issues.

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Genetics & Epigenetics of Alzheimer's and Parkinson's Disease

Posted by Tuesday, 4 March 2014 , , , , ,

Despite the fact that Alzheimer’s (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases, their pathogenesis still remains largely not well understood. However, advances during the last few decades in the characterizations of rare mendelian mutations and common risk genes as well as the role of epigenetics have greatly enhanced our understanding for the role of heritability and environmental factors in the development of AD and PD. This paper reviews key findings along their molecular mechanisms while tries to provide an overview of the overall contribution of genetics and epigenetics in the two diseases. Moreover, recent findings on neuronal genetic instability are also mentioned and, finally, a model that tries to integrate the effects of genetics, epigenetics, environment and pathological processes is proposed supporting the hypothesis that few ‘seeding’ pathogenic foci are sufficient to produce generalized pathology.



Introduction and Insight from Twin Studies. 


Alzheimer’s (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases affecting about 1% and 0.5-1% in 65-69 years old and up to 50% and 4% respectively in older groups.[1-3] The pathogenesis of the two diseases is heterogeneous and not well understood although the long-standing involvement of specific protein misfolding and aggregation is well characterised in each case. AD presents as an insidious and progressive deterioration of global cognitive functions and is histopathologically recognized by the accumulation of extracellular amyloid-β-containing (Aβ) plaques and intraneuronal deposits of hyperphosphorylated τ protein (pτ) in the form of neurofibrillary tangles (NFTs). Both soluble/prefibrillar and fibrillar Aβ together with pτ are highly implicated in axonal transport failure, deranged dendritic signalling, excitotoxicity and ultimately cell death.[4,5] Similarly, in PD, which predominantly but not solely affects the dopaminergic system leading to a wide range of motor and neuropsychiatric symptoms, α-synuclein-containing intraneuronal Lewis bodies (LBs) are considered hallmark of the disease,[6,7] while the role of deranged protein handling, ubiquitin proteasome system (UPS) and mitochondrial dysfunction, and increased oxidative stress are considered to be pivotal.[8,9] 

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'Rewiring' the Parkinsonian Brain. Challenges in Cell Replacement Therapies for Parkinson's Disease.

Posted by Wednesday, 20 November 2013 , , , , , , ,

This article was written in Nov 2013 for my course. 

Abstract                                                                                          
Parkinson’s disease (PD) has been considered as a disease leading to debilitating motor symptoms due to the progressive focal death of dopaminergic neurons in the substantia nigra (SN). Different therapeutic strategies aiming to restore this dopaminergic network with transplantation of a variety of cells have yielded promising results both in the lab and the clinic and offered a definite proof of principle. Yet, even though clinical trials have shown that restoration of dopamine is feasible, have many times failed to produce significant and meaningful benefits and, moreover, they are often complicated by variability and the development of new abnormal motor symptoms. This has not only led to a very fertile discussion about the issues that need to be overcome but also to the realisation that new perspectives are needed towards both cell replacement therapies and PD. Understanding that cell transplantation creates novel conditions not found in the premorbid or morbid brain, while appreciating the widespread effects of PD which cannot be reduced in the focal loss of dopaminergic cells, maybe perhaps the only way to overcome the inherent obstacles posed to cell replacement therapies in PD and to further develop novel therapeutic strategies.

Introduction
Parkinson’s Disease (PD) is classically considered as a progressive, neurodegenerative disease that manifests itself clinically with the cardinal triad of tremor, bradykinesia (difficulty in initiating and executing muscle movement) and rigidity, as a result of extensive loss of dopaminergic neurons (60-80%)[1, 2] located in a part of the midbrain called substantia nigra pars compacta (SNc). SNc neurons innervate the putamen of the striatum and both are part of a complex neural circuit involved in modulating movement (see figure 1 and [3,4]). However, PD’s pathophysiology is multifactorial and not well understood[5; for a brief review] and even if the involvement of other parts of the brain producing motor and non-motor symptoms is recognised (see later), most current therapeutic approaches aim principally in the restoration of the dopamine levels (e.g. administration of levodopa) and amelioration of the related symptoms. Nonetheless, the presumed neuropathological specificity of PD: the focal loss of a single cell type innervating a particular structure, made it an excellent candidate for cell replacement therapy (CRT) with the ultimate view of replacing neuronal losses and restoring neuronal circuitry to the premorbid status.[6]


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Multiple Sclerosis, K+ Channels and potential therapeutic strategies

Posted by Saturday, 19 October 2013 , , , , , ,

Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a very strong autoimmune component. Its name is a descriptive term and originates from the observation of multifocal lesions/plaques in the CNS. These lesions of variable size usually involve the white matter of the brain (myelinated axons) but can extend to gray matter too (where the neuronal cell bodies are found) According to WHO the global incidence and prevalence are estimated to be 2.5 per 100,000 person-­‐years and 30 per 100,000 persons respectively. MS is a very complex disease with tremendous variability both in its presentation (as any brain areas can be affected potentially giving rise to any neurological symptom) and its clinical course. Its aetiology and pathogenesis is not well understood but, as twin studies have shown, genetic factors may account for 25 to 75%  and this leads to the hypothesis that environmental triggers may be implicated in the pathogenesis of MS in susceptible individuals carrying certain genes. 
This post is based on an essay I wrote for my course in 2012. It explores the differences between myelinated and non-myelinated axons, the consequences of demyelination and possible therapeutic strategies targeting certain potassium channels. 


Introduction
The integrity of multiple sclerosis (MS) as a single nosological entity is threatened with strong evidence highlighting its pathophysiological and clinical heterogeneity. The pathogenesis of MS is not well understood and its classification as an autoimmune disease has also been questioned (Kornek, Lassmann 2003, Ludwin 2006, Ludwin, Raine 2008) The recognition of four immunohistologically distinct patterns in addition to the recognized variable response to immunomodulatory therapy, indicates the need for therapies directed to either the potentially variable underlying pathophysiology or the ubiquitously detrimental effects of demyelination. Despite the fact that many aspects of MS pathophysiology need to be elucidated, MS can still be defined as “a chronic inflammatory disease of the central nervous system (CNS)” characterized by focal demyelination and partial axonal sparing (Kornek, Lassmann 2003). The role of ion and especially potassium channels in both axonal failure and T-cell activation is pivotal and could provide a basis for the treatment of MS and other neuroinflammatory or demyelinating diseases. Hence, this essay is going to be focused on the neurophysiology of action potential (AP) conduction and the potential of potassium channels as therapeutic targets.


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EyeWire: Mapping the brain connectome while connecting people.

Posted by Tuesday, 1 October 2013 , , , ,

Three years after Azevedo et al (2009) dissolved a couple of human brains into a soup in order to obtain a more accurate estimate of the total number of neurons in the human brain ( a still staggering figure of 86.1 +/- 8.1 billions), Dr. Sebastian Seung and his team in MIT decided to go the other way in order to figure out how exactly these 86 bn neurons are connected with each other.
It is generally accepted that the exact wiring of all these neurons, the connectome, is that which really constraints neural activity - which neurons interact with which -  and by extension that which underlies all information processing and computing taking place in the brain. And many researchers like Seung take this further and support that it is the connectome that really makes us who we are.
So far, many ways have been tried in order to map the brain connectome: from diffusion MRI studies, which provide a large scale picture of neuron connectivity - but with very little resolution, to multiple stains microscopy techniques, which can provide good resolution but which are, limited to just a few cells. Yet again, the estimated number of synapses of the human brain is unimaginable; just the neocortex (20 bn neurons) has about 150 trillions of them (Pakkenberg 1997; 2003) and this definitely makes the mapping of a single brain connectome a titanic endeavour. 

For this reason Seung's team decided to focus their investigation on the mapping of a retina that was sliced by a microtome and scanned by electron microscopy in order to digitally reconstruct its neurons. However, this is a task that no computer can do alone (at least today) and it takes up to 50hrs in order to reconstruct a single neuron. Computers are prone to many errors when analysing such data. Hence, it would take centuries to reconstruct an adequate number of them if it weren't for the power that can be harnessed from the crowds!
Seung and his team devised the EyeWire platform, a platform which allows 1000s non-expert gamers to spend their time - literally - constructively by mapping the projections of certain retinal neurons called JAM-B cells. These cells are characterised by direction-selectivity and hence respond specifically to upward motion (in the visual field) and can by distinguished from others by a protein called Junctional Adhesion Molecule B (JAM-B) which gave them their name. Interestingly the cells themselves show some topographic asymmetry and this raises many questions about the relationship between their structure/connections and their function. But is not just that: understanding the connections of these cells may give us a great insight not only in how vision works but also in many conditions including blindness. 


So far, more than 80.000 gamers from 130 countries have joined, making EyeWire a great example of "citizen science" and emphasising the significance of not only making science accessible to the community but also of increasing people's participation. Evermore, the 1000s of work-hours spent every day by gamers do not only contribute into the reconstruction of the retinal cells but are also used in order to train computers to process these data more efficiently. The potential of this project is truly full of promises. 

You can learn more about EyeWire and play the game here:






Athanasios Alexandris



Azevedo, F. A. et al (2009). Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J. Comp. Neurol. 513, 532–541.
Pakkenberg, B., et al (2003). Aging and the human neocortex. Exp. Gerontology, 38:95-99, 
Pakkenberg, B.et al. (1997) Neocortical neuron number in humans: effect of sex and age. J. Comp. Neurology, 384:312-320, 1997.

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Αθανάσιος Αλεξανδρής