Reply to “Controversies over the staging of α-synuclein pathology in Parkinson’s disease”

Abstract

(1) The authors Wnd fault with two of our papers [3, 8], claiming that they “suVer from a fundamental problem in experimental design”. In total, 413 brains were screened in the Wrst study [8]. In all of these cases the substantia nigra was examined for incidental Lewy pathology (LP) because this region is required for the neuropathological diagnosis of sporadic Parkinson’s disease (PD). LP was seen in the dorsal vagal motor nucleus (30/30) and olfactory bulb/stalk (16/30) in 30 of these cases. Fifty-eight controls were examined, i.e., virtually two ageand gender-matched controls for each case with incidental LP. From both the 30 incidental cases and the 58 controls, sample tissue blocks were taken from all of the known PD predilection sites. Two peer reviewers and the previous JNEN editor understood the study design of the Wrst paper correctly and found it to be adequate. The incidental and control groups were expanded and described in subsequent papers [3–5]. (2) The authors state that “it is not clear why involvement of the substantia nigra was not found in any of the ‘incidental’ (sic) Lewy body disease cases described by the Braak group in Del Tredici et al. 2002” and reiterate this two additional times under their second point. In fact, the presence of LP was reported in the substantia nigra of 4/30 incidental cases (see Table 2: cases 20, 27, 29, 30) [8]. The Wnding also appears under the subheading “Lesions in the Substantia Nigra following (p. 421) and in the caption accompanying Fig. 3 (p. 422) [8]. Thus, the authors’ statements concerning nigral involvement of incidental cases are inaccurate. (3) The authors remark that it is “important to note that a correlation of neuronal loss with Syn burden is not considered in the Braak et al. [3] paper.” Our retrospective autopsy-based staging paper was intended to evaluate disease progression based on the anatomical distribution pattern of LP in the brain; the study design did not include statistical correlations. Disease progression in sporadic PD includes, but is by no means limited to, neuronal loss (e.g., in the dorsal vagal motor nucleus, reticular formation, locus coeruleus, substantia nigra, basal nucleus of Meynert, intralaminar thalamic nuclei) [3, 11, 13–15, 21, 28, 33, 34]. Overemphasis of the criterion neuronal loss is too limited because it fails to take into consideration signs of neuronal dysfunction short of nerve cell death. In the absence of biological markers and universally accepted neuropathological criteria for PD, neuropathologists, pathologists, and brain bankers have the marker Syn, upon which other Lewy body staging protocols have been based [19, 20, 22, 24, 30, 32]. More recently, the studies by Beach et al. and Dickson et al. have shown that reduced tyrosine hydroxylase levels in the striatum and in epicardial sympathetic nerves in cases with incidental LP may be markers for preclinical PD [2, 9]. In a third study, LN density in epicardial nerves of incidental and PD cases correlated well with Hoehn & Yahr staging as well as with our staging system [12]. H. Braak (&) · K. Del Tredici Institute for Clinical Neuroanatomy, J.W. Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany e-mail: braak@em.uni-frankfurt.de