Changes in the solubility and phosphorylation of α-synuclein over the course of Parkinson's disease.

Lewy bodies are made from insoluble, phosphorylated α-synuclein, but the earliest changes that precipitate such pathology still remain conjecture. In this study, we quantify and identify relationships between the levels of the main pathologic form of phosphorylated α-synuclein over the course of Parkinson's disease in regions affected early through to end-stage disease. Brain tissue samples from 33 cases at different disease stages and 13 controls were collected through the Australian Network of Brain Banks.

Alpha-synuclein redistributes to neuromelanin lipid in the substantia nigra early in Parkinson's disease.

The distribution and tempo of neuronal loss in Parkinson's disease correlates poorly with the characteristic and more widely spread intracellular changes associated with the disease process (Lewy bodies and Lewy neurites). To determine early intracellular changes in regions where cell loss is most marked (dopaminergic A9 substantia nigra) versus regions with Lewy bodies but where cell loss is limited, we assessed 13 patients with definite Parkinson's disease at various disease stages in comparison with controls. Using immunohistochemistry for alpha-synuclein, we confirmed the concentration of this protein in the soma of normal A9 neurons and in Lewy body pathology in brainstem catecholamine neurons in Parkinson's disease.

Insoluble alpha-synuclein in Alzheimer's disease without Lewy body formation.

Insoluble alpha-synuclein plays a central role in Lewy body diseases, with considerable controversy as to whether it plays a similar role in Alzheimer's disease (AD). We assessed the tissue location and solubility of cortical alpha-synuclein in AD (without Lewy body formation) compared with controls, using sequential extraction procedures and Western immunoblotting to quantify different alpha-synuclein species in their different solubility states. Controls had no insoluble cortical alpha-synuclein and a ratio of soluble:lipid-associated alpha-synuclein of 1.

Clinicopathological correlates in frontotemporal dementia.

The term frontotemporal dementia (FTD) encompasses a range of clinical syndromes that are believed not to map reliably onto the spectrum of recognized pathologies. This study reexamines the relationships between clinical and pathological subtypes of FTD in a large series from two centers (n = 61). Clinical subtypes defined were behavioral variant FTD (n = 26), language variants (semantic dementia, n = 9; and progressive nonfluent aphasia, n = 8), and motor variants (corticobasal degeneration, n = 9; and motor neuron disease, n = 9), although most cases presented with a combination of behavioral and language problems.

Astrocytic degeneration relates to the severity of disease in frontotemporal dementia.

The main unifying feature of cases with frontotemporal dementia (FTD) is the pattern of brain atrophy. Surprisingly, there are a variety of underlying histopathologies in cases with the clinical features and typical pattern of atrophy characterizing FTD. This suggests that the degenerative mechanism(s) associated with pyramidal cell loss and gliosis in FTD is likely to be similar in the different histopathological forms of the disease.