Nigrostriatal Dopaminergic Activities in Dementia with Lewy Bodies in Relation to Neuroleptic Sensitivity: Comparisons with Parkinson’s Disease Margaret A. Piggott, Elaine K. Perry, Elizabeth F. Marshall, Ian G. McKeith, Mary Johnson, Heather L. Melrose, Jennifer A. Court, Stephen Lloyd, Andrew Fairbairn, Andrew Brown, Peter Thompson, and Robert H. Perry Background: In dementia with Lewy bodies (DLB) mild extrapyramidal symptoms are associated with moderate reductions in substantia nigra neuron density and concen- tration of striatal dopamine. Many DLB patients treated with typical neuroleptics suffer severe adverse reactions, which result in decreased survival. Methods: In a series of DLB cases, with and without neuroleptic sensitivity, substantia nigra neuron densities, striatal dopamine and homovanillic acid concentrations, and autoradiographic [ 3 H]mazindol and [ 3 H]raclopride binding (to the dopamine transporter and D2 receptor, respectively) were analyzed and compared to control and idiopathic Parkinson’s disease cases. Results: D2 receptors were up-regulated in neuroleptic- tolerant DLB and Parkinson’s disease compared to DLB without neuroleptic exposure and controls. D2 receptors were not up-regulated in DLB cases with severe neuro- leptic reactions. Dopamine uptake sites were reduced concomitantly with substantia nigra neuron density in Parkinson’s disease compared to controls, but there was no significant correlation between substantia nigra neu- ron density and [ 3 H]mazindol binding in DLB groups. There was no significant difference in substantia nigra neuron density, [ 3 H]mazindol binding, and dopamine or homovanillic acid concentration between neuroleptic-tol- erant and -sensitive groups. Conclusions: Failure to up-regulate D2 receptors in response to neuroleptic blockade or reduced dopaminer- gic innervation may be the critical factor responsible for neuroleptic sensitivity. Biol Psychiatry 1998;44: 765–774 © 1998 Society of Biological Psychiatry Key Words: Dementia with Lewy bodies, Parkinson’s disease, neuroleptic sensitivity, D2 receptors, dopamine uptake sites, dopamine, substantia nigra Introduction D ementia with Lewy bodies (DLB) (McKeith et al 1996) is a progressive dementia typically presenting with variable combinations of confusion, behavioral dis- turbance, extrapyramidal symptoms, hallucinations, and fluctuating cognitive impairment, developing rapidly to severe and persistent cognitive deficits (McKeith et al 1992; Hansen et al 1990; Kuzuhara and Yoshimura 1993). DLB is characterized neuropathologically by the presence of cortical and brain stem Lewy bodies, with variable Alzheimer-type pathology and moderate loss of dopami- nergic neurons in the substantia nigra (Perry et al 1990), which is not as extensive as the loss found in Parkinson’s disease. Mild extrapyramidal signs may be present spon- taneously, which can be severely exacerbated, or appear for the first time, following the administration of typical neuroleptic drugs prescribed to control the hallucinatory symptoms and associated behavioral disturbances. These responses to neuroleptics vary from mild, represented by an increase in Parkinsonism that resolves upon drug withdrawal, to much more severe reactions, sometimes giving rise to symptoms such as rigidity, semiconscious- ness, pyrexia, postural hypotension, falling, increased confusion, sudden collapse, and rapid deterioration to death (McKeith et al 1992). Adverse responses of this type have been interpreted as evidence of neuroleptic sensitiv- ity, which increases patient mortality threefold. Such severe reactions are seldom seen in patients with Alzhei- mer’s disease without Lewy body pathology (McKeith et al 1992). These symptoms can be similar in some in- stances to the neuroleptic malignant syndrome (Bristow and Kohen 1993), where proposed etiologies have in- cluded malfunctioning monoamine metabolism (Nisijima From the Neurochemical Pathology Unit, Medical Research Council, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom. Address reprint requests to Dr. Margaret A. Piggott, Neurochemical Pathology Unit, Medical Research Council, Newcastle General Hospital, Westgate Road, Newcastle Upon Tyne NE4 6BE, United Kingdom. Received September 13, 1995; revised March 3, 1996; revised July 10, 1997; revised March 2, 1998; accepted March 6, 1998. © 1998 Society of Biological Psychiatry 0006-3223/98/$19.00 PII S0006-3223(98)00127-9