Amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease: phylogenetic disorders of the human neocortex sharing many characteristics.

Features common to amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) are reviewed. Shared epidemiological aspects include an increasing frequency which is proportional for each disease. We draw attention to geographic non-uniform distribution which, for ALS and PD, correlates positively with latitude. Clinical and pathological overlap occurs in the same patients, and in members of the same family. A high early morning plasma cysteine/sulphate ratio possibly related to the development of proteinacious inclusions, as well as ubiquinated neuronal inclusions, characterize ALS, PD and AD. HLA-DR (the human group II major histocompatibility class) staining is marked in ALS, PD and AD and may represent autoimmunity-incited by-products of neuronal degeneration. Based upon demonstrated glutaminergic connections between the neocortex and anterior horn cells, the entorhinal cortex and the basal ganglia we hypothesize that ALS, AD and PD are phylogenetic disturbances of the neocortical cell. The postsynaptic neuron may degenerate secondarily to anterograde effects of deranged glutamate metabolism. Future therapeutic strategies should be directed to agents that decrease transmission induced by excitatory amino-acids.