Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease.

OBJECTIVE: To determine whether evidence of neuronal dysfunction or demise preceded deposition of Lewy pathology in vulnerable neurons in Parkinson disease (PD). METHODS: We examined the extent of nigral dysfunction and degeneration among 63 normal, incidental Lewy body disease (ILBD), and PD cases based on tyrosine hydroxylase (TH) immunoreactivity and neuron densities, respectively. The relationship between these markers and Lewy pathology (LP) burden in the substantia nigra (SN) and Braak PD stage was assessed. RESULTS: Compared with normal subjects, ILBD cases displayed a significantly higher percentage of TH-negative cells and lower neuronal densities in the SN as early as Braak PD stages 1 and 2, before LP deposition in the nigrostriatal system. ILBD nigral neuron densities were intermediate between normal subjects and PD cases, and TH-negative percentages were higher in ILBD than either normal or PD cases. Furthermore, neuron density and neuronal dysfunction levels remained relatively constant across Braak PD stages in ILBD. CONCLUSIONS: These results suggest that significant neurodegeneration and cellular dysfunction precede LP in the SN, challenging the pathogenic role of LP in PD and the assumption that ILBD always represents preclinical PD.

Brain organochlorines and Lewy pathology: the Honolulu-Asia Aging Study.

Although organochlorines have been reported more frequently in Parkinson's disease (PD) brains than in controls, the association with brain Lewy pathology is unknown. Honolulu-Asia Aging Study (HAAS) participants, exposed to organochlorines from a variety of sources during midlife, represent a population well suited to determining the relationship of brain organochlorines with Lewy pathology in decedents from the longitudinal HAAS. The study design included the measurement of 21 organochlorine levels in frozen occipital lobe samples from HAAS decedents. Alpha-synuclein immunostaining performed on 225 brains was used to identify Lewy bodies and Lewy neurites. With the potential for spurious associations to appear between Lewy pathology and 17 organochlorine compounds found in at least 1 brain, initial assessments identified heptachlor epoxide isomer b, methoxychlor, and benzene hexachloride b as being most important. The prevalence of Lewy pathology was 75% (6 of 8) among brains with any 2 of the 3 compounds, 48.8% (79 of 162) among those with 1, and 32.7% (18 of 55) for those with neither (P = .007 test for trend). Although findings persisted after removing cases with PD and dementia with Lewy bodies and after adjustment for age at death, body mass index, pack-years of cigarette smoking, and coffee intake (P = .013), the results were insignificant when correcting for multiple testing. Although consistent with earlier accounts of an association between organochlorines and clinical PD, associations with Lewy pathology warrant further study.

Evaluation of alpha-synuclein immunohistochemical methods used by invited experts.

The use of alpha-synuclein immunohistochemistry has altered our concepts of the cellular pathology, anatomical distribution and prevalence of Lewy body disorders. However, the diversity of methodology between laboratories has led to some inconsistencies in the literature. Adoption of uniformly sensitive methods may resolve some of these differences. Eight different immunohistochemical methods for demonstrating alpha-synuclein pathology, developed in eight separate expert laboratories, were evaluated for their sensitivity for neuronal elements affected by human Lewy body disorders. Identical test sets of formalin-fixed, paraffin-embedded sections from subjects diagnosed neuropathologically with or without Lewy body disorders were stained with the eight methods and graded by three observers for specific and nonspecific staining. The methods did not differ significantly in terms of Lewy body counts, but varied considerably in their ability to reveal neuropil elements such as fibers and dots. One method was clearly superior for revealing these neuropil elements and the critical factor contributing to its high sensitivity was considered to be its use of proteinase K as an epitope retrieval method. Some methods, however, achieved relatively high sensitivities with optimized formic acid protocols combined with a hydrolytic step. One method was developed that allows high sensitivity with commercially available reagents.

Falling in Parkinson disease: identifying and prioritizing risk factors in recurrent fallers.

OBJECTIVES: To identify falling risk factors in a study population of recurrent fallers compared with nonfallers who have Parkinson disease, and to prioritize falling risk factors in this patient population to target them for modification. DESIGN: Twenty-three recurrent fallers and 25 nonfallers who have Parkinson disease were recruited, and they participated in a comprehensive assessment probing for the presence of falling risk factors. To identify falling risk factors, a group comparative design was used to compare recurrent fallers and nonfallers across an array of variables. To prioritize those risk factors, modeling using recursive partitioning was performed, entering into the model falling, risk factors identified in this and other studies that were considered potentially modifiable. RESULTS: A specific profile of variables distinguished recurrent fallers who have Parkinson disease in our study population: higher disease severity, higher level of motor impairment, higher level of disability, impaired leg agility or lower-limb coordination, impaired ability to arise from a chair or compromised proximal lower-limb motor control, impaired ambulation, impaired motor planning of the hands and feet, impaired dynamic balance as measured by ability to walk in tandem, and fear of falling. Recursive partitioning prioritized three risk factors: impaired ambulation, impaired lower-limb motor planning, and orthostasis. CONCLUSIONS: In this study, an idiosyncratic falling risk factor profile was demonstrated among our subjects who have Parkinson disease. Three variables were prioritized for potential modification: impaired ambulation, impaired lower-limb motor planning, and orthostasis.