Over 100 years ago, Robert Koch introduced his ideas about how to prove a causal relationship between a microorganism and a disease. Koch's postulates created a scientific standard for causal evidence that established the credibility of microbes as pathogens and led to the development of modern microbiology. In more recent times, Koch's postulates have evolved to accommodate a broader understanding of the host-parasite relationship as well as experimental advances. Techniques such as in situ hybridization, PCR, and representational difference analysis reveal previously uncharacterized, fastidious or uncultivated, microbial pathogens that resist the application of Koch's original postulates, but they also provide new approaches for proving disease causation. In particular, the increasing reliance on sequence-based methods for microbial identification requires a reassessment of the original postulates and the rationale that guided Koch and later revisionists. Recent investigations of Whipple's disease, human ehrlichiosis, hepatitis C, hantavirus pulmonary syndrome, and Kaposi's sarcoma illustrate some of these issues. A set of molecular guidelines for establishing disease causation with sequence-based technology is proposed, and the importance of the scientific concordance of evidence in supporting causal associations is emphasized.

Whipple's disease of the central nervous system (CNS) may be associated with normal intestinal histology as a result of minimal or patchy involvement. The diagnosis is difficult and is frequently made post mortem. We studied 6 patients with clinically suspected CNS Whipple's disease; 2 had oculomasticatury myorhythmia (OMM) fitting criteria for a diagnosis of definite CNS Whipple's disease. One of the 2 had duodenal histology highly suggestive of Whipple's disease the other 5 patients had normal duodenal histology. DNA was extracted from paraffin-embedded duodenal tissues in all patients and frozen pontine tissue in 1. Two primer pairs (W3F-W4R, W3F-W2R) were used in separate polymerase chain reactions (PCRs) to amplify fragments of Tropberyma whippelii 16S rDNA from these tissue samples. PCR amplicons were detected only in the duodenal tissues from the 2 patients with OMM. The sequences of these amplicons were identical to the corresponding region of the previously published Tropheryma whippelii 16S rDNA sequence. PCR-based assays of intestinal or brain tissue may be of value for confirming, and possibly refuting, a clinical diagnosis of CNS Whipple's disease in a patient with any combination of dementia, supranuclear gaze palsy, hypothalamic manifestations, myoclonus, seizures, ataxia, or OMM, especially when tissue histology is unrevealing.

Background : PD psychosis is often associated with cognitive impairment, including dementia, and involves dopaminergic, serotonergic, and cholinergic mechanisms. Objective : To evaluate the differential effect of the antipsychotic pimavanserin, a selective serotonin 2A receptor inverse agonist, in PD psychosis patients with versus without cognitive impairment and in those receiving versus not receiving cognitive‐enhancing medications. Methods : Data from the pivotal randomized clinical trial of pimavanserin for PD psychosis were stratified by (1) screening MMSE score as cognitively impaired (21‐24) versus unimpaired (≥25) and (2) concomitant use versus nonuse of cognitive‐enhancing medications. The primary outcome measure was change in the PD‐adapted Scale for the Assessment of Positive Symptoms. Results : Mean (pimavanserin vs. placebo) change from baseline was larger in the cognitively impaired (n = 50; –6.62 vs. –0.91; P = 0.002) versus the cognitively unimpaired (n = 135; –5.50 vs. –3.23; p = 0.046) group. The comparable change was –6.04 versus –2.18 ( P = 0.012) and –5.66 versus –3.15 ( P = 0.041) in patients treated (n = 69) and not treated (n = 116) with concomitant cognitive‐enhancing medication. Pimavanserin was similarly tolerated across all cognitive groups with no additional safety concerns identified. Overall adverse event rates were comparable across the concomitant cognitive‐enhancing medication groups; however, rates of serious adverse events and discontinuations attributed to adverse events were increased in patients taking cholinesterase inhibitors. Conclusions : The antipsychotic effect of pimavanserin is robust in PD patients with cognitive impairment and may be enhanced by concomitant cognitive‐enhancing medication use. Future prospective studies are needed to confirm these preliminary findings. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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