Structural basis of dementia in neurodegenerative disorders

Progressive dementia syndromes in adults are caused by a number of conditions associated with different structural lesions of the brain. In most clinical and autopsy series, senile dementia of the Alzheimer type is the most common cause of mental decline in the elderly accounting for up to 90%, whereas degenerative non-Alzheimer dementias range from 7 to 30% (mean 8-10%). They include a variety of disorders featured morphologically by neuron and synapse loss and gliosis, often associated with cytopathological changes involving specific cortical and subcortical circuits. These neuronal/glial inclusions and neuritic alterations show characteristic immunoreactions and ultrastructure indicating cytoskeletal mismetabolism. They are important diagnostic sign posts that, in addition to the distribution pattern of degenerative changes, indicate specific vulnerability of neuronal populations, but their pathogenic role and contribution to mental decline are still poorly understood. In some degenerative disorders no such cytopathological hallmarks have been observed; a small number is genetically determined. While in Alzheimer's disease (AD) mental decline is mainly related to synaptic and neuritic pathologies, other degenerative disorders show variable substrates of dementia involving different cortical and/or subcortical circuits which may or may not be superimposed by cortical Alzheimer lesions. In most demented patients with Lewy body disorders (Parkinson's disease, Lewy body dementia), they show similar distribution as in AD, while in Progressive Supranuclear Palsy (PSP), mainly prefrontal areas are involved. Lobar atrophies, increasingly apparent as causes of dementia, show fronto-temporal cortical neuron loss, spongiosis and gliosis with or without neuronal inclusions (Pick bodies) and ballooned cells, while dementing motor neuron disease and multisystem atrophies reveal ubiquitinated neuronal and oligodendroglial inclusions. There are overlaps or suggested relationships between some neurodegenerative disorders, e.g. between corticobasal degeneration, PSP and Pick's atrophy. In many of these disorders with involvement of the basal ganglia, degeneration of striatofrontal and hippocampo-cortical loops are important factors of mental decline which may be associated with isocortical neuronal degeneration and synapse loss or are superimposed by cortical AD pathology.