Selective cell loss in Edinger-Westphal in asymptomatic elders and Alzheimer’s patients L.F.M. Scinto a,d, *, M. Frosch b,d , C.K. Wu c , K.R. Daffner a,d , N. Gedi c C. Geula c,d a Department of Neurology, Laboratory of Higher Cortical Functions, Brigham and Women’s Hospital, Boston, MA 02115, USA b Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA c Laboratory for Neurodegenerative and Aging Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA d Harvard Medical School, Boston MA 02115, USA Received 3 November 2000; received in revised form 19 February 2001; accepted 6 March 2001 Abstract Exaggerated pupillary response to a low concentration of cholinergic antagonists has been suggested as an early marker for Alzheimer’s Disease (AD). To examine the anatomic basis of this phenomenon, we determined possible neuropathological changes in the Edinger- Westphal (EW) nucleus, a midbrain neural center with a significant functional role in the control of pupil size. Stereologically determined neuronal numbers within the EW were counted in individuals with pathologically confirmed AD, control cases with no AD-type pathology, and subjects with AD pathology not meeting diagnostic criteria for AD. The EW of AD patients displayed a marked and striking neuronal loss when compared with controls. In contrast, the number of neurons in the somatic portion of the nucleus of the third cranial nerve (NCNIII) remained intact. The EW in brains from clinically normal individuals with evidence of early AD-type pathology also displayed a significant and selective loss of neurons. The magnitude of EW neuronal loss in the latter group was smaller than that observed in AD. These findings suggest that pupillary hypersensitivity in AD may be caused by abnormalities in the EW. Neuronal loss and pathology within the EW in a subpopulation of clinically silent controls with pathologic findings consistent with early-stage AD constitutes a possible explanation for the reported exaggerated pupil response in some normal elderly subjects. © 2001 Elsevier Science Inc. All rights reserved. Keywords: Alzheimer disease; Edinger-Westphal nucleus; Immunohistochemistry; Neuronal loss; Tangles; Pupillary reflex; Stereology 1. Introduction Our search for a mechanism to explain the exaggerated pupil dilation response [39] of Alzheimer’s disease (AD) patients and some community dwelling elders to dilute tropicamide led us to the possibility that the observed hy- persensitivity might be linked to pathology in the Edinger- Westphal (EW) nucleus. The EW is the efferent neural center for the control of pupillary function, and along with the somatic subdivision, forms the nucleus of cranial nerve three (NCNIII). Animal studies [20,22] have demonstrated that the parasympathetic preganglionic efferent output for pupillary response originates in the EW. This small-celled autonomic division of the NCNIII lies medial and dorsal to the somatic subdivision of this nucleus in the midbrain. The EW is located ventral to the periaqueductal gray matter (PAG) and extends from the level of the caudal pole of the red nucleus to the region of nucleus interstitialis, a distance of approximately 5 mm [35]. The EW receives input from the retina via the pretectum [8] and sends its axons through the oculomotor nerve to the ciliary gan- glion [26,8]. In animals, injections of cholinergic agents into this region have been shown to affect the size of the pupil [41]. Based on the above anatomic and functional consider- ations, it seemed likely that the EW might be a target for pathological changes that could lead to the observed hyper- sensitivity of the pupil in AD. Previous studies at our lab- oratory have established that, in contrast to the somatic division of the NCNIII, the EW is a specific and early target for Alzheimer’s pathology [40]. Specifically, a significant density of plaques and particularly tangles were observed in the EW of AD patients and a subpopulation of clinically normal individuals with cortical plaques and tangles. The present study examined the presence of neuronal loss in the EW these cases. * Corresponding author. Tel.: +1-617-732-8068; fax: +1-617-713- 3066. E-mail address: lscinto@rics.bwh.harvard.edu (L.F.M. Scinto). www.elsevier.com/locate/neuaging Neurobiology of Aging 22 (2001) 729 –736 0197-4580/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S0197-4580(01)00235-4