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Do -synuclein aggregates in autonomic plexuses predate Lewy body disorders?

A cohort study

From the Departments of Neurology (A.M.-C., F.E.-S., A.O.-M.), Pathology and Tumor and Tissue Bank (C.E.C., A.C.), and Nuclear Medicine (A.C.R., M.G.-R.), Virgen de las Nieves University Hospital, Granada, and Tissue Bank for Neurological Research (D.G.M.), Madrid, Spain; and St. Michael's Hospital (D.G.M.), University of Toronto, Ontario, Canada.

Address correspondence and reprint requests to Dr. A. Mínguez-Castellanos, Servicio de Neurología, Hospital Universitario Virgen de las Nieves, CRT 3ª planta, Carretera de Jaén s/n, 18013 Granada, Spain aminguezc{at}meditex.es

Objective: To determine the prevalence of -synuclein (AS) aggregates in abdominopelvic autonomic plexuses in the general population and to evaluate the relationship between this finding and the subsequent development of neurologic dysfunction.

Methods: First, surgical specimens from 100 patients (ages 44 to 84) undergoing a wide resection of an abdominopelvic organ were examined by anti-AS immunostaining. Second, 16 patients (6 AS+ and 10 randomly selected AS–) participated in yearly double-blinded neurologic assessments.

Results: AS aggregates were found in autonomic plexuses in 9% of the whole sample (95% CI 3.4 to 14.6%) but were more common in vesicoprostatic (26%) than in digestive tract (4%) specimens. At 16 months after the biopsy, no prevalent cases of Parkinson disease, dementia, or autonomic failure were diagnosed among participants. One AS+ patient had previously been diagnosed with REM sleep behavior disorder. Seven of 10 control subjects but none of the 6 AS+ patients had a diagnosis of hypertension (p = 0.01). During phase IV of Valsalva maneuver, AS+ group exhibited a longer blood pressure recovery time (p = 0.03), with one patient showing absence of blood pressure overshoot. Cardiac [¹²³I]metaiodobenzylguanidine uptake was reduced in the AS+ group (p = 0.03). Striatal [¹²³I]ioflupane uptake was abnormally low in only one AS+ patient. At 30 months after the biopsy, lower cardiac and striatal uptake values tended to correlate with higher Unified Parkinson's Disease Rating Scale III scores (p = 0.07).

Conclusion: The common presence of -synuclein aggregates in peripheral autonomic neurons may represent an early presymptomatic phase in the development of Lewy body disorders.

*These authors contributed equally to this work.

Supported by grants from "Fundacion Virgen de las Nieves," "Consejeria de Salud" of the Andalusian Government (189/02), and "Instituto Carlos III" of the Spanish Government (FIS 0310/03; Red CIEN C03/06).

Disclosure: The authors report no conflicts of interest.

Received May 31, 2006. Accepted in final form February 5, 2007.

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