Neurological diseases can be classified as neurodegenerative, inflammatory dysfunction, vascular, tumor and functional, according to mechanisms that are in their essence. Of course, besides the fact that he can not claim to be exhaustive, this classification is criticized because he is constantly developing with the advancement of knowledge. For the record, Parkinson's disease is long considered neurosis before it is discovered that the degeneration of dopamine producing cells causes motor symptoms that are one of the features. With the evolution of neuroscience and their foreseeable progress over the next twenty years, our vision of mechanisms that are based on neurological diseases, as well as our ability to anticipate, prevent and treat patients in a holistic manner will greatly vary. epidemiology, knowledge of environmental impacts, molecular genetics, cellular bioinformatics, multiscale capture. Here we will discuss the current state of knowledge, problems and challenges of the most common neurological diseases. Among the two neurodegenerative pathologies, the two most common are Parkinson's and Alzheimer's. Amiotrophic lateral sclerosis is less common, but on the other hand it is particularly difficult.
Motional symptoms – tremor, rigidity and slow volunteer movements (bradykinia) – are characteristic of the disease and have long been considered as only clinical manifestations. Only for forty years after the first clinical description of James Parkinson (1817), the lack of dopamine synthesis caused by neuronal degeneration in brain brain was identified as responsible for these motor symptoms. After Carlsson proved the concept of rabbit in 1957, it is necessary to wait another ten years for the first therapeutic use of L-dopamine dopamine precursor to compensate for this deficit. If this replacement therapy brings a certain benefit to motor symptoms at the onset of the disease, this is a burden of exhaustion of efficiency in more advanced forms and complications, especially motor and behavioral ones. In 1987, Grenoble's Benabid team first demonstrated the efficacy of stimulation of thalamus nucleus, chlamydia, electronically chipped to the brain (deep brain stimulation or SCP) on tremor. Seven years later, the same team shows that the stimulation of the subthalamic nucleus generally improves motor symptoms of the disease. Though deep brain stimulation is indicated only in a relatively small percentage of patients, and treatment, which has no side effects, this approach has shown that the function of a deficit neuronal network can be renewed even in the absence of dopamine and was a real revolution in treating the disease.
Today, the dopaminergic neuronal system remains the target of SCP treatment, new targets (inner globus pallidus, pedunculate pontine nucleus) and new functional surgical techniques (focal lesions by radiofrequency or ultrasound) have been proposed. The pharmacological arsenal extends to molecules targeting subpopulations of dopaminergic receptors or non-dopaminergic systems, particularly in the correction of non-motoric symptoms (cognitive decline, hallucinations, depression, apathy, sleep disorders, obsessive-compulsive disorders). Parkinson's disease is not just a motor disease, and many non-motoric symptoms are present in most patients. Some testify of dysfunction of dopaminergic control (circle of emotions and behaviors), but many others are related to the achievement of non-dopaminergic neuronal circles. Interestingly, some of these symptoms (anosis, constipation, sleep disturbances, depression) can be preceded by cardinal motor symptoms, which now speak of the prodromal stage of the disease, revealing the possibility of preventing motor phase phenomena in the event of early intervention.
Accumulation of abnormal inclusions (Lewy's body) in dopaminergic cells substantia nigra has been known since the early 20th century. In 1997, a protein-encoding mutation, alpha-sinuklein, was identified in a rare form of autosomal dominant Parkinson's disease. Researchers have shown that Lewy's bodies contain a large amount of alpha-sinuklein, which puts it in one of the important candidates for the death of neurons. It has been shown that the accumulation of alpha-sinuklein and Lewy's bodies can be observed in the brain of subjects without Parkinson's disease, in addition to the dark matter, especially in the scented nuclei and the lower part of the brain stem. Parkinson's disease is actually the evolutionary stage of alpha-sinukleinopathy that begins in the scented nucleus and dorsal nucleus of the vaginal nerve (pneumo-gastric) to then affect the brain stem cells involved in regulating the sleep / wake cycle (raphe nuclei [séroto‑ninergiques] and locus coeruleus [noradrénergique]before reaching the black substance). This model, suggested by Braak and his colleagues in 2002, will explain why certain impotent symptoms (reduced smell ability, constipation, blood pressure disorders, and sleep disorders) are often preceded by the emergence of the first signs. This would also explain the beginning of the late stage of cognitive impairment by advancing alpha-sinukleinopathy to the cortical level. Since discovery of alpha-sinuklein, more than ten mutations in other genes have been identified, recessive or dominant, indicating different molecular mechanisms (mitochondrial dysfunction, lack of protein degradation by lysosomes). …) that are involved in 10% of the family's disease patterns and testify to the complex nature of mechanisms that lead to neuronal degeneration in Parkinson's disease.
One of the major challenges of the next 20 years is to illuminate the cause of alpha-sinuklein buildup in the brain, and there are arguments for its out-of-brain search. If, as we have seen, the accumulation of alpha-sinuklein begins in the fragrant bulb and the intestinal nervous system, it remains to be clarified as this protein protein expands from the periphery to the central nervous system. , then within it, following the paths that link the target structure, among which the black substance. The potential role of environmental factors (herbicides, pesticides, metals …) in the onset of Parkinson's disease, the influence of changes in microbes are all traces.
A common disease with an increased frequency and frequency of years, Alzheimer's disease is associated with a cognitive impairment that initially affects memory, specific histological lesions (extracellular amyloid plaques, neurofibrilar degeneration and amyloid angiopathy) associated with loss of neurons. , His cause remains unknown. The lesions contain the β-amyloid protein aggregates, the cleavage product of the transmembrane protein, whose function is unknown (amyloid precursor protein or APP), and Tau protein, a hyperphosphorylated cytoskeletal protein in Alzheimer's disease.
Unlike the lack of dopamine in Parkinson's disease, no deficiency in neurotransmission does explain cognitive disorders. The most significant improvement over the last ten years is the confirmation of clinical criteria and biomarkers that allow early diagnosis of the disease.
The weight of genetic factors is not the same in the early (65 years old) and later (after 65 years) forms, which makes up 5% and 95% of the cases. In early forms, several mutations of genes that encode the proteins involved in APP metabolism and gene A? Amyloid protein have been identified. These mutations have high penetration (85%), mainly in autosomal dominant mode and are considered diagnostic biomarkers of family forms of early disease.
In later forms, the risk is twice as high for the development of illnesses in the first-degree cousins of patients who are themselves ill. For almost 25 years, the presence of APOE e4, one of three alleles encoding apolipoprotein E, has been confirmed as a genetic risk factor. The presence of allele APOEe4 doubles the risk, and the two copies are multiplied by five. Collaborative extensive genome research has established about 20 other genes related to the disease. Some of the proteins encoded by these genes can be involved in known molecular mechanisms of the disease, such as APP metabolism; others intervene at the level of the nervous system in the immune response, endocytosis (mechanism of intracellular molecular incorporation), or angiogenesis, which represents as many pathways to research new physiopathological mechanisms. Knowing these risk factors for a non-cure disease poses serious ethical issues that have already been set up to detect APOEe4 genes.
The degenerative process involved in Alzheimer's disease begins several years before the onset of the symptoms. During this presymptomatic phase, it is likely that treatment that aims to delay the course of the disease will most likely be effective. Identification of the biomarker of the disease, whose sensitivity and specificity now confirm at an early stage, was a major step forward in the conduct of therapeutic trials.
Currently available markers are: i) loss of medium temporal lobe structure (hippocampus, entorhinal cortex and amygdala), which is visible to MRI and whose quantification methods are constantly being developed; ii) Biochemical markers CSF: low concentration of amyloid P1-42 protein, high concentration of total Tau protein or hyperphosphorylated Tau protein; iii) metabolic markers that can be objectified by functional neuropicture: reduction of glucose metabolism in PET in temporoparietal regions, visualization of amyloid accumulation by PET ligand (PIB); iv) genetic markers such as the presence of autosomal dominant mutations (see above).
Over the past fifteen years, more than 400 clinical trials have been conducted without convincing results. Compensation of drugs that inhibit acetylcholine esterase or NMDA receptor antagonists has just been interrupted in France. Promising immunization results against Apl-42 protein on mouse transgenic model resulted in discontinuous vaccination in humans for adverse effects. Phase II monoclonal antibody targeting aimed at the ß-amyloid or phospho-Tau protein has been initiated and 112 therapeutic agents in the Phase I-III probationary pathway were recently identified,
Activities promoting social integration, psychological support and the development of reception facilities in local communities managed by multidisciplinary teams are another priority. Neuroscientific research does not lack these social approaches, it contributes to the progress of remediation as a means to delay the progression of cognitive disorders.
Excerpt from the book Etienne Hirsch and Bernard Poulain, "The Brain in Light," published by Odile Jacob.
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