Parkinson's disease is a common neurodegenerative disease. Although the exact etiology and natural course of this disease have yet to be fully clarified, numerous system-level processes and dysfunctions, have been implicated in the pathogenesis of Parkinson's disease.

Lipid droplets are highly dynamic organelles that emerge from the endoplasmic reticulum (ER) membrane. lipid droplets is involved in fatty acid storage and participate in many diseases. For example, myeloid cells, including macrophages, leukocytes, and eosinophils, form lipid droplets in response to inflammation and stress.

Normally, intracellular lipid droplets are degraded in lysosomes and deliver fatty acids to mitochondria for their consumption as an alternative energy source during periods of nutrient depletion. However, neurons have a low capacity for mitochondrial fatty acid consumption for energy production. This characteristic makes neurons particularly sensitive to lipid droplet accumulation and peroxidation.

Furthermore, the accumulation of lipid droplets enhances the fatty acid oxidation rate and imposes persistent pressure on the mitochondrial electron transport chain. Lipid overload also leads to ROS production by oxidative enzymes. Emerging evidence indicates that unexpected lipid droplet deposition and peroxidation can accelerate organelle stress and plays a crucial role in the pathogenesis of neurodegenerative diseases.

In a previous study, Xiaojuan Han and colleagues found that kaempferol, a natural flavonoid small molecule, exhibited neuroprotective effects on mice with drug-induced Parkinson's disease.

In the current study, the authors showed in-vitro that kaempferol protected against tyrosine hydroxylase neuronal loss and behavioral deficits in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinson disease mice, accompanied by reduced lipid oxidative stress in the substantia nigra pars compacta.

Kaempferol-rich food has been linked to a decrease in the risk of developing some types of cancers and cardiovascular disease. Quercetin and kaempferol are among the most ubiquitous polyphenols in fruit and vegetables.

Kaempferol is a chemical produced by Kaempferia galanga, one of four plants called galangal. The extract of Kaempferia galanga causes central nervous system depression, a decrease in motor activity, and a decrease in respiratory rate.

The mice were treated with kaempferol. The rotarod performance time was markedly reduced in MPTP-treated mice, and this effect was prevented by kaempferol. kaempferol also restored the behavioral deficits induced by MPTP, as indicated by the reductions in the turning time and total time in the pole test, without affecting the body weights of the mice.

MPP+, the active metabolite of MPTP, inhibits mitochondrial complex enzymes and causes the cell death that is directly associated with PD. In cultured neuronal cells, kaempferol exhibited a relatively safe concentration range and significantly suppressed lipid droplet accumulation and cellular apoptosis induced by MPP.

Further studies indicated that the protective effect of kaempferol was dependent on autophagy, specifically lipophagy. Critically, kaempferol promoted autophagy to mediate lipid droplet degradation in lysosomes, which then alleviated lipid deposition and peroxidation and the resulting mitochondrial damage, consequently reducing neuronal death.

Furthermore a genetic knockdown abolished the neuroprotective effects of kaempferol against lipid oxidation in Parkinson disease mice.

This work demonstrates that kaempferol prevents dopaminergic neuronal degeneration in Parkinson disease via the inhibition of lipid peroxidation-mediated mitochondrial damage by promoting lipophagy and provides a potential novel therapeutic strategy for Parkinson disease and related NDDs.

Parkinson’s disease (Parkinson’s disease) is a major neurodegenerative disorder. It currently lacks a clinically relevant treatment that can directly target the disease-causing processes. Current clinical approaches, like deep brain stimulation and pharmacological treatments with levodopa and dopamine agonists, only relieve symptoms. The efficacy of these treatments is largely limited by their undesirable complications and side effects. Source: By Ajpolino via Wikipedia

Since α-synuclein is overexpressed under certain pathological conditions of PD and these upregulated proteins can interfere with many physiological processes, such as ER-to-Golgi transport, synaptic transmission, and mitochondria function and morphology, robustly knocking down the overexpressed α-synucleinmay have better neuroprotective efficacy in restoring normal cellular functions in the Parkinson’s disease brain than simply inhibiting the formation of toxic α-synuclein oligomers.

Knockdown of α-synuclein using genetic manipulations, such as antisense oligonucleotide and small interfering RNA (siRNA), has shown protection of dopaminergic neurons in various models of Parkinson’s disease.

The clinical translation of these manipulations into an efficient Parkinson’s disease therapy has however costly and uncomfortable, as it is mainly accomplished by an invasive injection or viral infection. These technologies may not be clinically practical for therapeutic use in human patients.

Here the scientists report the development of a short, BBB and plasma membrane-permeant synthetic peptide that can rapidly reduce endogenous α-synuclein via proteasomal degradation.

Using both in vitro and in vivo models of Parkinson’s disease, the scientists provide proof-of-principle evidence for using this small α-synuclein knockdown peptide as a potential Parkinson’s disease therapy.

The authors first demonstrated that the Tat-βsyn-degron peptide can specifically reduce the level of α-synuclein both in vitro and in vivo. The authors then showed that the peptide-induced α-synuclein knockdown is associated with protection of dopaminergic neurons against toxin-induced damage in a culture model of Parkinson’s disease.

Most importantly, the scientists were able to demonstrate the therapeutic potential of systemic application of the Tat-βsyn-degron peptide as an effective Parkinson’s disease treatment in two well-characterized animal models of Parkinson’s disease.

Their α-synuclein knockdown peptide (Tat-βsyn-degron) is innovative as the peptide directly targets one of the disease-causing processes, and can be expected to stop or slow down the progression of the disease.

In addition, the peptide-mediated knockdown has a clear temporal advantage over antisense or siRNA-mediated knockdown. α-synuclein is a very stable protein with a long half-life while by hijacking the endogenous proteasomal degradation system in the cell, the Tat-βsyn-degron peptide produced a rapid and robust degradation of α-synuclein protein within a few hours.

It is also interesting to note that α-synuclein is also expressed in tissues outside the central nervous system and the scientists found that a single intraperitoneal injection of the Tat-βsyn-degron peptide similarly reduced the α-synuclein expression in the kidney and the spleen of wild-type C57BL/6 mice .

A recent success in a phase 3 clinical trial has already demonstrated that a Tat-fused short peptide is not only safe, but therapeutically effective in protecting neurons against ischemic damage in humans. The authors hope this α-synuclein knockdown peptide may also have the potential to be quickly translated into the clinic as an effective disease-modifying treatment that directly targets the disease-causing process of Parkinson’s disease.

Due to the versatility of their peptide-mediated protein knockdown method, the scientists can theoretically target disease-causing cellular proteins by simply changing the protein-binding sequence of the targeting peptide. Since many human diseases, including some of the age-related neurodegenerative diseases such as ALS, Alzheimer’s disease and Huntington’s disease, are pathologically caused by gain of function of a protein due to its mutations and/or increased expression levels, the proposed study can be expected to spur the development of new therapeutics for human diseases beyond Parkinson’s disease.

Advertisement

This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

A study which has just been published in the leading neurology journal Brain, indicates that Parkinson's disease is not one but two diseases, starting either in the brain or in the intestines.

These two groups of patients displayed strikingly different profiles on multimodal imaging battery.

These profiles support the existence of a brain-first and body-first subtype of Parkinson’s disease, and furthermore, that premotor rapid eye movement sleep (REM) sleep behaviour disorder is a highly predictive marker of the body-first subtype.

Neuropathological autopsy studies of patients with Parkinson’s disease, dementia with Lewy bodies, or incidental Lewy body disease have shown discrepant results.

Heiko Braak’s staging system was derived from a cohort of patients, who were selected based on the presence of Lewy pathology in the dorsal motor nucleus of the vagus, and all these patients conformed to a brainstem predominant type.

Other studies reported that some post-mortem cases do not harbour Lewy pathology in the dorsal motor nucleus of the vagus, and a minority of patients do not follow the Braak staging scheme.

A pathological hallmark of Parkinson’s disease is the presence of intraneuronal a-synuclein inclusions termed Lewy pathology. However, it remains unknown from where the initial a-synuclein aggregates originate.

It has been hypothesized that a-synuclein inclusions initially form in nerve terminals of the enteric nervous system, and then subsequently spread via autonomic connections to the dorsal motor nucleus of the vagus and intermediolateral cell columns of the sympathetic system (Braak et al., 2003).

In addition, Lewy pathology has been detected in gastrointestinal nerve fibres years prior to Parkinson’s disease diagnosis. There is also epidemiological evidence that complete but not partial vagotomy may protect against later Parkinson’s disease.

Autopsy studies have shown that a minority of cases with Lewy pathology do not have pathological inclusions in the dorsal motor nucleus of the vagus, and that a fraction of cases display a limbic-predominant distribution of a-synuclein inclusions with less pathology in the brainstem.

The scientists hypothesized that the appearance of isolated REM sleep behaviour disorder well before parkinsonism is a strong marker of the body-first subtype. The presence of REM sleep behaviour disorder in the premotor phase is a marker of the body-first type, probably a reflection of ascending a-synuclein pathology reaching the pons before the substantia nigra. The substantia nigra in the brain. Source Wikipedia

To test this hypothesis, they recruited de novo patients with Parkinson’s disease and performed video-polysomnography to divide patients into de novo Parkinson’s disease without REM sleep behaviour disorder and de novo Parkinson’s disease with pre-motor REM sleep behaviour disorder. The study was conducted between August 2018 and January 2020.

The scientists have shown that prodromal and de novo patients with Parkinson’s disease can be categorized by means of multimodal imaging into distinct clusters, which are compatible with a brain-first and body-first Parkinson’s disease subtype.

Their conclusion is that the Parkinson’s disease comprises two subtypes: (i) a body-first (bottom-up) subtype, where the pathology originates in the enteric or peripheral autonomic nervous system, and then ascends via the vagus nerve and sympathetic connectome to the CNS;

(ii) a brain-first (top-down) subtype, in which the a-synuclein pathology initially arises in the brain itself or sometimes enters via the ol- factory bulb, and subsequently descends to the peripheral autonomic nervous system.

Body-first (bottom-up) subtype: The initial a-synuclein pathology appears in the enteric or peripheral autonomic nervous system. It then propagates via the sympathetic connectome to the heart, and via the vagus nerve to the dorsal motor nucleus of the vagus. The pons area in the brain. Source Wikipedia

Ascending pathology affects pontine structures giving rise to REM sleep behaviour disorder before the substantia nigra shows substantial involvement. When parkinsonism appears, signifying a loss of 450% of nigrostriatal dopamine terminals, all lower Braak stage structures show marked damage on relevant imaging markers.

Brain-first (top-down) subtype: In the brain-first type, the initial a-synuclein pathology appears in the CNS. The most likely site of origin seems to be the amygdala or connected structures, or the pathology may in some cases enter via the olfactory bulb. Rarely, the pathology arises in the upper brainstem (substantia nigra or locus coeruleus). The pathology spreads from the site of origin to the brainstem and cortex. When parkinsonism appears, the brainstem shows a rostro-caudal gradient of pathology with marked involvement of the substantia nigra, moderate involvement of the neighbouring pons, but little involvement of the medulla and autonomic nervous system.

Citation: Jacob Horsager et al, Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study, Brain (2020). DOI: 10.1093/brain/awaa238

Parkinson's disease is characterized by a loss of dopaminergic neurons in the substantia nigra. There is no treatment that can improve the course of Parkinson's disease. While most treatment strategies are aimed at preventing neuronal loss or protecting neural circuits, a potential alternative, is to replace lost neurons to reconstruct altered neural circuits.

Given the plasticity of some somatic cells, transdifferentiation approaches to change the fate of cells (in situ as escape the immune system) have gained momentum. In the brain of mice, the plasticity of glial cells has thus been used to generate new neurons which have shown an improvement in disease in model animals.

Most in vivo reprogramming relies on the use of transcription factors specific to the cell line under consideration. This study shows that there are other ways to achieve this goal.

Researchers from the University of California (UC), San Diego School of Medicine, have developed a non-infectious virus that carries an antisense oligonucleotide sequence designed to specifically bind to RNA encoding the PTB protein, degrading it, preventing it from being translated into a functional protein. Antisense oligonucleotides are a proven therapeutic approach.

Sequential downregulation of PTB and nPTB occurs naturally during neurogenesis, and once triggered, the gene expression loops regulated by PTB and nPTB become self-reinforcing. By modulating the two loops, the sequential negative regulation of PTB and nPTB makes it possible to generate functional neurons from human fibroblasts.

Astrocytes offer several benefits for in vivo reprogramming in the brain. These non-neuronal cells are abundant, proliferate when injured and are very plastic. They can adopt different phenotypes or even be reprogrammed in a very different cell type. Astrocytes can be converted into different neural subtypes, depending on their region of origin in the brain.

Here, scientists from the University of California, San Diego School of Medicine, report an efficient, single-step conversion of astrocytes from humans and mice into functional neurons. This by depleting the RNA-binding protein PTB (also known as PTBP1).

The target cells for this conversion are the dopaminergic neurons in the substantia nigra, that is, those that become non-functional in Parkinson's disease. Using this approach, the team demonstrated the gradual conversion of astrocytes into new neurons capable of innervating and repopulating the neural circuits of the substantia nigra. These dopaminergic neurons induced by depletion of the PTB powerfully restore striatal dopamine, restore the nigrostriatal circuit and reverse the motor phenotypes of Parkinson's disease.

In treated mice, a subset of about 30% of the astrocytes were converted to neurons, thus increasing the total number of neurons. Dopamine levels were restored to a level comparable to that of normal mice. In addition, neurons have developed and sent their processes to other parts of the brain. There was no change in the control mice.

The treated mice recovered their vitality with a single treatment and remained completely free of Parkinson's symptoms for the rest of their lives. In contrast, control mice did not show any improvement.

To experiment with the conversion of midbrain astrocytes to dopaminergic neurons, the scientists used a model of chemically induced Parkinson's disease in mice. The model used by the team does not perfectly summarize all the essential characteristics of Parkinson's disease. In the future, scientists will use a more expensive animal genetic model of Parkinson's.

One could wonder if this therapy can be transposed to other neurodegenerative diseases. However, Parkinson's disease is characterized by an illness in a very specific region of the brain. On the contrary, in Alzheimer's disease, the damage is global to the brain and in the case of amyotrophic lateral sclerosis the neurons involved are the motor neurons, but they cover a considerable area.

Advertisement

This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

La maladie de Parkinson se caractérise par une perte de neurones dopaminergiques dans la substantia nigra. Il n’existe aucun traitement pouvant améliorer le cours de la maladie de Parkinson. Alors que la plupart des stratégies de traitement visent à prévenir la perte neuronale ou à protéger les circuits neuronaux, une alternative potentielle, mais non explorée jusqu’à maintenant, consiste à remplacer les neurones perdus pour ainsi reconstruire les circuits neuronaux altérés.

Compte tenu de la plasticité de certaines cellules somatiques, les approches de transdifférenciation pour changer le destin des cellules (in situ pour échapper au système immunitaire), ont pris de l’ampleur. Dans le cerveau de souris, la plasticité des cellules gliales a ainsi été mise à profit pour générer de nouveaux neurones ayant montrés une amélioration de maladie chez les animaux modèles.

La plupart des reprogrammations in vivo reposent sur l’utilisation de facteurs de transcription spécifiques à la lignée de cellule considérée. Cette étude montre qu’il existe d’autres moyens pour atteindre cet objectif.

Des chercheurs de l'Université de Californie ont développé un virus non infectieux qui porte une séquence d’oligonucléotides antisense conçue pour se lier spécifiquement à l’ARN codant pour la protéine PTB, la dégradant ainsi, l’empêchant d’être traduit en une protéine fonctionnelle. Les oligonucléotides antisense sont une approche thérapeutique éprouvée.

La régulation négative séquentielle de PTB et nPTB se produit naturellement pendant la neurogenèse, et une fois déclenchée, les boucles d’expression génique régulées par PTB et nPTB deviennent auto-renforçantes. En modulant les deux boucles, la régulation négative séquentielle de PTB et nPTB permet de génèrer des neurones fonctionnels à partir de fibroblastes humains.

Les astrocytes offrent plusieurs avantages pour la reprogrammation in vivo dans le cerveau. Ces cellules non neuronales sont abondantes, prolifèrent en cas de blessure et sont très plastiques. Elles peuvent adopter différents phénotype, voire être reprogrammées dans un type de cellule très différent. Les astrocytes peuvent être convertis en différents sous-types neuronaux, suivant leur région d’origine dans le cerveau.

Ici, les scientifiques rapportent une conversion efficace en seule étape, d’astrocytes issus d’humains et de souris, en neurones fonctionnels. Ceci en appauvrissant la protéine de liaison à l’ARN PTB (également connue sous le nom de PTBP1). Les cellules cibles de cette conversion sont les neurones dopaminergiques (DA) dans la substantia nigra, c’est-à-dire ceux qui deviennent non fonctionnels dans la maladie de Parkinson. En appliquant cette approche, les scientifiques ont démontré la conversion progressive des astrocytes en nouveaux neurones capables d’innerver et repeupler les circuits neuronaux de la la substantia nigra. Ces neurones dopaminergiques induits par l’épuisement du PTB rétablissent puissamment la dopamine striatale, reconstituent le circuit nigrostriatal et inversent les phénotypes moteurs de type maladie de Parkinson.

Chez les souris traitées, un sous-ensemble d’environ 30% des astrocytes, se sont convertis en neurones, augmentant ainsi le nombre total de neurones. Les niveaux de dopamine ont été restaurés à un niveau comparable à celui des souris normales. De plus, les neurones se sont développés et ont envoyé leurs processus dans d’autres parties du cerveau. Il n’y a eu aucun changement chez les souris témoins.

Les souris traitées ont récupérées leur vitalité avec un seul traitement et sont restées complètement indemnes de symptômes de la maladie de Parkinson pour le reste de leur vie. En revanche, les souris témoins n’ont montré aucune amélioration.

Pour expérimenter la conversion des astrocytes du mésencéphale en neurones dopaminergiques, les scientifiques ont utilisé un modèle de la maladie de Parkinson chimiquement induit chez la souris. Le modèle utilisé par l’équipe ne résume pas parfaitement toutes les caractéristiques essentielles de la maladie de Parkinson. À l’avenir, les scientifiques utiliseront un modèle génétique animal plus coûteux de Parkinson.

On peut se demander si cette thérapie est transposable à d’autres maladies neurodégénératives. Cependant la maladie de Parkinson est caractérisée par une atteinte dans une région très spécifique du cerveau. Au contraire dans la maladie d’Alzheimer l’atteinte est globale au cerveau et dans le cas de la sclérose latérale amyotrophique les neurones impliqués sont les neurones moteurs mais cela recouvre une zone géographique considérable, qui s’étend largement hors du système immunitaire central.

Publicité

Ce livre retrace les principales réalisations de la recherche sur la SLA au cours des 30 dernières années. Il présente les médicaments en cours d’essai clinique ainsi que les recherches en cours sur les futurs traitements susceptibles d’ici quelques années, d’arrêter la maladie et de fournir un traitement complet en une décennie ou deux.

A new study aimed to determine the effect that learning to walk on a treadmill with a rhythm provided by an external signal, could then have on walking on the floor in people with Parkinson's disease.

Functional magnetic resonance imaging (fMRI) studies have shown decreased activation in many locomotor areas of the brain in people with Parkinson's disease. This decreased activation impairs the ability to change the pace of walking. The use of external signals reduces the pressure on the internal regulation of walking timing.

The use of rhythmic auditory signals improves gait parameters in people with Parkinson's disease. Rhythmic auditory signals presumably serve as an external stimulus and alleviate the alteration of internal synchronization in Parkinson's disease.

It is important to note that the literature is closely focused on the use of faster tempo. This is probably due to the fact that most investigators seek to increase the speed of walking in order to increase the motor capacity of the sick. In addition, it has been suggested that the use of slower frequencies increases the risk of falls.

The walking speed is a function of both the cadence and the length of the step. Thus, when walking on the floor, the cadence changes induced by the auditory signals can increase the speed of walking, but without requiring a patient to increase the length of his steps.

The authors hypothesize that on a treadmill, people with Parkinson's disease will increase the step length with a slow-tempo metronome signal (85% of normal tempo) due to the fixed speed of the treadmill, and will keep this length of their step on the ground with a fast-tempo metronome signal (which increases the perception of their speed).

Indeed, the authors observed that the stride lengths were longer when walking with slow time signals on the treadmill only, while the stride length was unchanged during walking on the floor.

These results probably come from a mixture of biomechanical and neuroanatomical mechanisms. The combined use of treadmill learning and rhythmic auditory signals can therefore improve the mechanics of walking on the floor, in a way that the patient could not have achieved independently.

Une nouvelle étude avait pour but de déterminer l'effet qu’un apprentissage de la marche sur tapis roulant avec un rythme fourni par un signal externe, pourrait avoir ensuite sur la marche sur le sol chez les personnes atteintes de la maladie de Parkinson.

Les études d'imagerie par résonance magnétique fonctionnelle (IRMf) ont démontré une diminution de l'activation dans de nombreuses zones locomotrices du cerveau chez les personnes atteintes de maladie de Parkinson. Cette activation diminuée, nuit à la capacité de modifier le rythme de la marche. L'utilisation de signaux externes diminue la pression sur la régulation interne du timing de la marche.

L'utilisation de signaux auditifs rythmiques permet d'améliorer les paramètres de démarche chez les personnes atteintes de maladie de Parkinson. Les signaux auditifs rythmiques servent vraisemblablement de stimulus externe et soulage l’altération de la synchronisation interne dans la maladie de Parkinson.

Il est important de noter que la littérature est étroitement axée sur l'utilisation de tempo plus rapide. Ceci est probablement dû au fait que la plupart des enquêteurs cherchent à augmenter la vitesse de la marche afin d’ugmenter la capacité motrice des malades. En outre, il a été suggéré que l'utilisation de fréquences plus lentes augmentait le risque de chutes.

La vitesse de marche est fonction à la fois de la cadence et de la longueur du pas. Ainsi, lorsqu'il marche sur le sol, les changements de cadence induits par les signaux auditifs peuvent augmenter la vitesse de la marche, mais sans obliger un patient à augmenter la longueur de ses pas.

Les auteurs émettent l'hypothèse que sur tapis roulant, les personnes atteintes de maladie de Parkinson augmenteront la longueur de pas avec un signal de métronome à tempo lent (85 % du tempo normal) en raison de la vitesse fixe du tapis, et conserveront cette longueur de leur pas sur le sol avec un signal de métronome à tempo rapide (ce qui augmente la perception de leur vitesse).

En effet, les auteurs ont observé que les longueurs de pas étaient plus longues lors de la marche avec des signaux de tempo lents sur le tapis roulant uniquement, tandis que la longueur de pas était inchangée pendant la marche sur le sol.

Ces résultats proviennent probablement d'un mélange de mécanismes biomécaniques et neuroanatomiques. L'utilisation combinée d'un apprentissage sur tapis roulant et de signaux auditifs rythmiques peut donc améliorer la mécanique de la marche sur le sol, d’une manière que le patient n’aurait pas pu obtenir de manière indépendante.

The description of minor hallucinatory phenomena (presence, passage hallucinations) has widened the spectrum of psychosis in Parkinson’s disease (PD). Minor hallucinations or delusions occur in approximately 50% of people with PD over the course of the illness, and may herald the emergence of dementia.

Patients say that the presences are not distressing, are short-lasting, and often are felt beside or behind them, while at home.

Such sensations have given rise to numerous literary and religious accounts. The first description of feeling of a presence by a psychologist was probably that of William James in 1902: “It often happens that an hallucination is imperfectly developed: the person affected will feel a ‘ presence ’ in the room, definitely localized, ( ... ) and yet neither seen, heard, touched, nor cognized in any of the usual ‘ sensible ’ ways . ”

Jaspers described the same phenomenon in 1913 under the name leibhaftige Bewusstheit : “There are patients who have a certain feeling or awareness that someone is close by, behind them or above them, someone that they can in no way perceive with the external senses, yet whose actual and concrete presence is clearly experienced ”.

Bleuler called “ extracampine ” a type of visual or tactile hallucination that occurs outside the limits of the sensory field. For example, a patient felt, on his skin, mice running on a wall, while another one “saw” birds or persons in a garden while seated in a room with his back to the window.

In a recent publication, the authors asked to 25 patients who endorsed presence phenomena, to complete a semi-structured interview about their experiences. The cognitive profiles of these patients were then compared to those of age- and education-matched patients who denied presence phenomena.

Patients described the presence as mostly that of an unknown human but without much interactions. Patients who described it as unpleasant were noted to also demonstrate elevated anxiety. Those patients who identified the presence as a known person, described it as touching them, or interacted with the presence emotionally or physically demonstrated reduced insight.

Presence phenomena were frequently associated impairments in visual processing, executive function and speed of processing and they may involve the posterior cortical functions. The experience is shaped by the patient's emotional state and level of understanding.

Advertisement

This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.