Most cases with Lewy pathology in a population-based cohort adhere to the Braak progression pattern but 'failure to fit' is highly dependent on staging system applied.

Braak et al.'s 2003 paper detailing the caudo-rostral progression of Lewy body pathology (LP) formed the foundation of current understanding of disease spread in Parkinson's disease (PD); however, its methods are difficult to recreate and consequently multiple new staging systems emerged to recapitulate Braak's staging system using standard neuropathological methods and to account for other patterns of LP. Studies using these systems have documented widely variable rates of cases that 'fail to fit' expected patterns of LP spread. This could be due to population differences, features of individual systems, or may constitute under-recognized patterns of disease. We examined 324 neuropathological cases from the Honolulu Asia Aging Study and applied four different LP staging systems to determine the proportion of cases adhering to different staging methodologies and those that 'fail to fit' expected patterns of LP. Of 141 cases with LP (24: PD, 8: Dementia with Lewy bodies (DLB), 109: Incidental Lewy body disease (ILBD)), our application of Braak et al., 2003 classified 83.7%, Müller et al., 2005 classified 87.9%, Beach et al., 2009 classified 100%, and Leverenz et al., 2008 classified 98.6%. There were significant differences in the cases classifiable by the Leverenz and Beach systems versus the Braak and Müller systems (p < 0.001 for each). In this population-based autopsy cohort with a high prevalence of ILBD, the majority of cases were consistent with the progression characterized by the Braak et al. however, the determination of cases as atypical is highly dependent on the staging system applied.

Laser light visual cueing for freezing of gait in Parkinson disease: A pilot study with male participants.

Freezing of gait (FOG) is a debilitating feature of Parkinson disease (PD). In this pilot study, we sought to assess the efficacy of a rolling walker with a laser beam visual cue to treat FOG in PD patients. We recruited 22 subjects with idiopathic PD who experienced on- and off-medication FOG. Subjects performed three walking tasks both with and without the laser beam while on medications. Outcome measures included time to complete tasks, number of steps, and number of FOG episodes. A crossover design allowed within-group comparisons between the two conditions. No significant differences were observed between the two walking conditions across the three tasks. The laser beam, when applied as a visual cue on a rolling walker, did not diminish FOG in this study.

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.

Falling risk factors in Parkinson's disease.

OBJECTIVE: To identify falling risk factors that are potentially modifiable among individuals who have idiopathic Parkinson's disease. DESIGN: A between group comparison of 19 fallers and 21 nonfallers who have Parkinson's disease, across an array of variables that have been identified as falling risk factors among the elderly and among those who have Parkinson's disease. RESULTS: Several variables were demonstrated significantly to distinguish fallers: disease duration and severity; dyskinesias associated with the use of dopaminergic agents; freezing; postural instability; depression; fear of falling; impaired fine motor control and motor planning in the feet; decreased proximal strength and muscular endurance in the legs; and a higher level of disability. CONCLUSIONS: Several of these variables can be viewed a potentially modifiable during a future intervention trial that aims to reduce falls in those who have Parkinson's disease using multidimensional risk factor modification.