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The past 20 years has witnessed tremendous progress in our understanding of Parkinson's disease. It is now well established that α-synuclein, a presynaptic neuronal protein, is not only a marker but also an actor of the disease. In this review, we discuss the advances that have been obtained in neuropathology using α-synuclein immunohistochemistry and the role of this protein in the spread of the disease., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Abnormalities of tau and alpha-synuclein have been described in a variety of neurodegenerative diseases often associated with sleep disorders. Neuropathological descriptions concerning these diseases are rapidly expanding, and they become difficult to summarise. On the other hand, the human neuroanatomy of sleep remains an ill defined issue. Main tauopathies are Alzheimer's disease, progressive supranuclear palsy, cortico-basal degeneration, argyrophilic grain disease, Pick disease and fronto-temporal degeneration with Parkinsonism associated with chromosome 17. In contrast to Alzheimer's disease, where abnormal tau containing cells are mainly neurones, in the other disorders, both neurones and glial cells are affected. The presynaptic protein alpha-synuclein is a major constituent of Lewy-type lesions in Parkinson disease and in dementia with Lewy bodies. Alpha-synuclein is also found in neurones and glia of Multi System Atrophy. This led to group these disorders into the still ill defined group of synucleinopathies. The lesions of tauopathies and synucleinopathies are presented, and their distribution in the most common disorders is described, distinguishing when possible neuronal loss and neuropathological markers. Recent data show that their extension is far larger than previously assumed and that they involve a variety of areas possibly involved in sleep regulation. Sleep disorders have been described in various tauopathies and synucleinopathies. However, no detailed clinico-pathological reports concerning the distribution of affected and spared areas in patients studied by polysomnography are available. Furthermore, the similarities of sleep disorders associated with different diseases, the interindividual variability, the frequently associated disorders, and the difficulties in quantifying neuronal loss make any clinicopathological correlation uncertain. The knowledge of sleep neuroanatomy is mainly based on animal studies. The few data concerning the structures of human brain areas involved in sleep organisation are recalled. Several systems known to be acting in sleep physiology are usually affected by tauopathies and synucleinopathies, but the pattern of their involvement in sleep pathology remains highly conjectural. The neuropathology of sleep disorders in tauopathies and synucleinopathies is a still uncultivated field.

The Lewy body, an eosinophilic inclusion around 10 microns in diameter, is localised in the neuronal perikaryon. Its dense core is surrounded by a clear halo, which is lacking in the so-called "cortical Lewy bodies". Numerous proteins have been identified in Lewy bodies, among which the three neurofilament isoforms, ubiquitin and proteasome subunits. More recently, alpha-synuclein--a pre-synaptic protein--has been found to be the essential constituent of the Lewy body. Alpha-synuclein antibody has greatly increased the sensitivity of the neuropathological examination: it has emphasized the frequency of "Lewy neurites" (accumulation of alpha--synuclein in neuronal processes) and has shown the importance of extra-nigral pathology. Lewy bodies and neurites are indeed to be found in many areas of the central and peripheral nervous system: stellate ganglia, cardiac and enteric plexus, pigmented nuclei of the brainstem, basal nucleus of Meynert, amygdala, limbic nuclei of the thalamus, parahippocampal and cingulate gyri, insula and isocortex. Lewy body diseases include at least three clinical syndromes: 1) idiopathic Parkinson disease in which the brainstem bears the brunt of the pathology 2) Parkinson disease dementia in which Lewy lesions are found in the brainstem and are also abundant in the isocortex. A large number of senile plaques is frequently associated. 3) In dementia with Lewy bodies, the same lesions are observed but the cognitive deficit occurs first or shortly (less than one year) after the motor symptoms.

Lewy bodies are intraneuronal inclusions initially found in the pigmented brainstem nuclei of patients with Parkinson's disease. Their aspect varies according to their neuronal or cerebral situation. They have been a long time the hallmark of Parkinson's disease, but in recent years it has emerged that a small group of rare disorders or rare variants of common degenerative diseases are also sometimes associated with Lewy bodies in the nervous system. Pathological studies have also individualized a new disorder characterized by the presence of numerous Lewy bodies throughout the cerebral cortex and the brainstem: Lewy body disease. The clinical syndrome associates dementia, parkinsonian features, dysautonomia and motor neuron disease. The dementia is cortical in type and psychiatric symptoms such as agitation, hallucinations or delusions are frequent. The pathological features are nerve cell loss, diffuse Lewy bodies, and sometimes senile plaques. The origin of this disorder remains unclear, but it could be a primitive abnormality of neuronal cytoskeleton.