Response to Parkinnen et al. and Jellinger

Abstract

We welcome the thoughtful letter from Parkinnen et al. We feel, however, that the ultimate role of medical scientiWc inquiry is to improve patient care and therefore it is by no means radical to bring suggested improvements in patient care before the scientiWc community for debate. Published literature indicates that deep brain stimulation (DBS) surgery is not without risk for serious complications and that the success of this intervention depends on the patient having PD. If this is so, olfactory bulb biopsy may prove useful and beneWcial in this setting. A percentage of surgical candidates could be spared a greater surgical risk (e.g. DBS) by undergoing a lesser surgical risk (olfactory bulb biopsy). Our comments regarding olfactory bulb biopsy are simply meant to stimulate dialogue on this topic. The authors question whether olfactory bulb biopsy could distinguish PD from MSA or PSP, especially since Lewy bodies may be present in sparse numbers in both of the latter two conditions. We have utilized olfactory bulb -synuclein stains in six MSA cases, and found all had numerous and characteristic Xame-shaped glial cytoplasmic inclusions, unambiguously identifying these as MSA. It may be more diYcult to distinguish PD from PSP. Our data show that 15 of 45 PSP cases had olfactory bulb Lewy bodies. Of these 15, the majority also had Lewy bodies in the brainstem and limbic region, suggesting that these subjects had both PD and PSP. Whether or not these subjects would diVer in surgical outcome from those with pure PD or pure PSP is not known at this time. We are currently testing methods for detecting glial tauopathy to determine whether these might positively identify PSP subjects from olfactory bulb material. In any case, accurate histological typing of DBS candidates would undoubtedly lead to beneWcial reWnements in surgical selection criteria. Aside from PSP and MSA, one might also question whether olfactory bulb biopsy could distinguish PD subjects from those with dementia with Lewy bodies (DLB) and from asymptomatic incidental Lewy body disease (ILBD). However, distinguishing between these disorders and PD is based on clinical presentation, not histopathology. The correlation coeYcients we reported between clinical measures and olfactory bulb synucleinopathy density scores are admittedly low but do not impact on diagnostic accuracy as we were employing a simple positive or negative dichotomy for those calculations. The accuracy of the clinical diagnosis of PD only rises above 80% after several years of observation and a clinical trial of levodopa, i.e. when PD is “end-stage”. As literature reports and our own data indicate that a large fraction of subjects with ILBD have olfactory bulb Lewy bodies (23/ 32 from our data), it appears probable that olfactory bulb Lewy bodies would be present in early clinical stages of PD and that olfactory bulb biopsy would extend a high clinical diagnostic accuracy, currently available only to those with advanced PD, to those at a much earlier stage. This is relevant in view of recent publications that may lead to early stage DBS or gene therapy for PD [4–6]. As early diagnosis and therapy is a major goal for all of the neurodegenerative diseases, olfactory bulb biopsy may oVer a practical route T. G. Beach (&) · M. N. Sabbagh · H. A. Shill Sun Health Research Institute, Sun City, AZ, USA e-mail: thomas.beach@sunhealth.org