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The ability of transdermal administration of the dopamine D2/D3 agonist piribedil (1-[3,4-methylenedioxybenzyl)]-4-[(2-pyrimidinyl)]piperazine) to reverse hypokinesia and other motor deficits observed in MPTP-treated common marmosets was investigated. Piribedil (2.5-10.0 mg/animal), applied directly to the skin of the abdomen as a paste, produced a long-lasting and concentration-dependent reversal of motor deficits. The antiparkinsonian actions of piribedil occurred within 10 minutes of drug administration and lasted as long as 10 hours. Transdermally applied piribedil produced a pattern of locomotor activity characteristic of normal motor behavior in this species. Symptoms of nausea (marked excessive salivation, retching, and/or vomiting) were not observed after transdermal application of piribedil. Additionally, pretreatment with the peripheral dopamine antagonist domperidone enhanced the antiparkinsonian effects of piribedil. Application to the skin of monolayer or bilayer patches impregnated with piribedil also produced a marked increase in locomotor activity and reversal of motor deficits. After application of various patch fractions (whole, one-half, or one-fourth), the increase in locomotor activity and reversal of disability correlated well with the surface area of skin covered. Measurement of serum levels of piribedil after single application of bilayer patches showed a positive relationship between drug levels and antiparkinsonian activity. Repeated daily application of piribedil bilayer patches for 5 days to MPTP-treated common marmosets primed to show dyskinesia by previous exposure to L-Dopa produced antiparkinsonian activity accompanied by dyskinetic movements. Transdermal administration of dopamine agonists such as piribedil may provide a useful means of producing a long-lasting reversal of motor deficits in Parkinson's disease while avoiding acute adverse effects such as nausea.

Disturbed circadian control of renal water excretion and blood pressure adaptation in Parkinson's disease (PD) suggest impaired hypothalamic magnocellular neurosecretion. To test the hypothesis that this may relate to specific hypothalamic pathology in PD, we studied morphometrically the neuronal population of the supraoptic nucleus (SON) in PD patients and controls. Neuronal loss in the SON of PD patients was associated with increased somatic, nuclear, and nucleolar size of remaining neurons, suggesting compensatory response of these cells. We conclude that SON pathology is a feature of PD and may account for specific signs of neurohumoral dysfunction.

Several studies have evaluated the reliability and validity of the clinical diagnosis of Alzheimer's disease (AD) using well-defined neuropathologic criteria, but none has attempted to evaluate the diagnostic accuracy of Pick's disease. We determined the accuracy of the clinical diagnosis of Pick's by presenting 105 autopsy-confirmed cases of Pick's (n = 7) and related disorders (non-Pick's, n = 98) as clinical vignettes in randomized order to six neurologists who were unaware of the autopsy findings. The group of raters had moderate to fair agreement for the diagnosis of Pick's as measured by the kappa statistics. The sensitivity for the diagnosis of Pick's for the first visit (mean, 53 months after onset) and last visit (mean, 78 months after onset) was low (range, 0 to 71%), but specificity was near-perfect. Median positive predictive values at both visits were 83 to 85%. False-negative misdiagnoses mainly involved AD. False-positive diagnoses were rare and occurred with corticobasal degeneration (first visit) and with dementia with Lewy bodies (last visit). Pick's was also misdiagnosed by primary neurologists. The best clinical predictors for the early diagnosis of Pick's included "frontal" dementia, early "cortical" dementia with severe frontal lobe disturbances, absence of apraxia, and absence of gait disturbance at onset. However, the first neurologic evaluation in some of the Pick's cases took place in advanced stages of the disease. Our findings suggest that this disorder is underdiagnosed in clinical practice. Although the low sensitivity for the clinical diagnosis of Pick's is disappointing, our data suggest that when clinicians suspect Pick's, their diagnosis is almost always correct. Absence of awareness of the main features of this disorder and of specificity of the frontal lobe syndrome may partially explain the low detection of Pick's disease.

The accuracy of the clinical diagnosis of corticobasal degeneration (CBD) is unknown. To determine its diagnostic accuracy, we presented 105 cases with known neuropathologic diagnoses, including CBD (n = 10), progressive supranuclear palsy (PSP, n = 24), Parkinson's disease (n = 15), diffuse Lewy body disease (n = 14), multiple system atrophy (n = 16), postencephalitic parkinsonism (n = 7), Pick's disease (n = 7), Creutzfeldt-Jakob disease (n = 4), Alzheimer's disease (n = 4), vascular parkinsonism (n = 3), and Whipple's disease (n = 1), as clinical vignettes to six neurologists unaware of the autopsy findings. Reliability was measured with the kappa statistics. The neurologists' clinical diagnoses were compared with clinicopathologic diagnoses for sensitivity, specificity, and positive predictive values at first and last clinic visits. The group reliability for the diagnosis of CBD significantly improved from moderate for the first visit (mean = 34 months after onset) to substantial for the last (68 months after onset). For the first visit, mean sensitivity for CBD was low (35%), but specificity was near-perfect (99.6%). For the last visit, mean sensitivity minimally increased (48.3%), and specificity remained stable. False-negative misdiagnoses mainly occurred with PSP. False-positive diagnoses were rare. The extremely low sensitivity of the clinical diagnosis of CBD suggests that this disorder is markedly underdiagnosed. Although the validity of the clinical diagnosis might have been improved if neurologists could have examined these patients, more important is that this disorder was misdiagnosed by the primary neurologists. In our data set, the best predictors for the diagnosis of CBD included limb dystonia, ideomotor apraxia, myoclonus, and asymmetric akinetic-rigid syndrome with late onset of gait or balance disturbances.

We assessed the validity and interrater reliability of neurologists who, using four different sets of previously published criteria for the clinical diagnosis of progressive supranuclear palsy (PSP), also called Steele-Richardson-Olszewski syndrome, rated 105 autopsy-proven cases of PSP (n = 24), Lewy body disease (n = 29), corticobasal ganglionic degeneration (n = 10), postencephalitic parkinsonism (n = 7), multiple system atrophy (n = 16), Pick's disease (n = 7), and other parkinsonian or dementia disorders (n = 12). Cases were presented in random order to six neurologists. Information from each patient's first and last visits to the medical center supplying the case was presented sequentially to the rater, and the rater's diagnosis was compared with the neuropathologic diagnosis of each case. Interrater agreement for the diagnosis of PSP varied from substantial to near perfect, but none of the criteria had both high sensitivity and high predictive value. Because of these limitations, we used a logistic regression analysis to identify the variables from the data set that would best predict the diagnosis. This analysis identified vertical supranuclear palsy with downward gaze abnormalities and postural instability with unexplained falls as the best features for predicting the diagnosis. From the results of the regression analysis and the addition of exclusionary features, we propose optimal criteria for the clinical diagnosis of PSP.