Parkinson disease (PD) is no longer considered a complex motor disorder characterized by Parkinsonism but rather a systemic disease with variegated non-motor deficits and neurological symptoms, including impaired olfaction, autonomic failure, cognitive impairment, and psychiatric symptoms. Many of these alterations appear before or in parallel with motor deficits and then worsen with disease progression. Although there is a close relation between motor symptoms and the presence of Lewy bodies (LBs) and neurites filled with abnormal -synuclein, other neurological alterations are independent of the amount of -synuclein inclusions in neurons and neurites, thereby indicating that different mechanisms probably converge in the degenerative process. Involvement of the cerebral cortex that may lead to altered behaviour and cognition are related to several convergent factors such as (a) abnormal -synuclein and other proteins at the synapses, rather than LBs and neurites, (b) impaired dopaminergic, noradrenergic, cholinergic and serotoninergic cortical innervation, and (c) altered neuronal function resulting from reduced energy production and increased energy demands. These alterations appear at early stages of the disease and may precede by years the appearance of cell loss and cortical atrophy. 1. Introduction Parkinson disease (PD) is clinically characterized by a complex motor disorder known as parkinsonism and is manifested principally by resting tremor, slowness of initial movement, rigidity, and general postural instability. These symptoms are mainly due to the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to reduced dopaminergic input to the striatum and accompanied by adaptive responses in the internal and external globus pallidus, subthalamus, thalamus and substantia nigra pars reticularis. Round, hyaline neuronal cytoplasmic inclusions called Lewy bodies (LBs) and enlarged aberrant neurites and threads are found in the Parkinsonian substantia nigra [1, 2]. In addition to the substantia nigra, other nuclei are involved such as the locus ceruleus, reticular nuclei of the brain stem, and dorsal motor nucleus of the vagus, as well as the basal nucleus of Meynert, the amygdala and the CA2 area of the hippocampus. LBs and aberrant neurites are also found in these locations [1–7]. Similar lesions but extended to the cerebral neocortex are characteristic of a closely-related disease named Dementia with Lewy bodies (DLB) [8]. PD and DLB are therefore considered Lewy body diseases (LBDs). Neuropathology and clinical aspects of DLB
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