Parkinson's disease (PD) has been considered a paradigm of degenerative diseases of the nervous system characterized by motor impairment (parkinsonism) due to malfunction and loss of dopaminergic neurons of the substantia nigra pars compacta. However, PD is a systemic disease of the nervous system with variegated clinical symptoms appearing before parkinsonism and due to the involvement of selected nuclei of the medulla oblongata, pons, autonomic nervous system and olfactory structures, among others. Furthermore, recent clinical data have shown modifications in behavior, personality changes and cognitive impairment leading to dementia. Lewy pathology, hallmark of PD, in the cerebral cortex does not correlate with cognitive impairment. However, recent studies have shown abnormal mitochondria content and function, and increased oxidative stress and oxidative responses in the cerebral cortex in PD. Furthermore, several key PD-related proteins are oxidatively damaged, including alpha-synuclein, beta-synuclein, superoxide dismutases, parkin, DJ1, UCHL1 and enzymes involved in glycolysis and energy metabolism. DNA and RNA are also targets of oxidative damage. Furthermore, abnormal phosphorylation of alpha-synuclein and tau occurs at the cortical synapses. Finally, abnormal cortical metabolism has been revealed with neuroimaging methods. These data demonstrate early involvement of the cerebral cortex in PD due to the convergence of multiple metabolic defects. Lewy pathology is a relative late event, geared to isolate unremoved damaged protein, with little significance on cortical neurological deficits.