Reply To: Cerebral Vasomotor Reactivity in Parkinson's Disease: A Missing Link between Dysautonomia, White Matter Lesions, and Cognitive Decline?

We appreciate the opportunity to respond to the comments on our article titled “White matter hyperintensities mediate impact of dysautonomia on cognition in Parkinson's disease”.1 We thank Dr. Castillo-Torres and colleagues for their feedback and perspective.2 We found their argument in line with, and further expanding, our findings, highlighting the substantial role of dysautonomia in the pathophysiology of early cognitive decline mediated via white matter hyperintensities (WMHs). The authors suggest that intrinsic pathologic alterations in patients with Parkinson's disease (PD) might disrupt cerebral dynamic autoregulation manifested as impaired cerebral vasomotor reactivity (CVR), which then predisposes patients to a higher WMH burden in response to orthostatic hypotension. This is indeed a viable hypothesis, in line with our findings on the primary role of dysautonomia in this pathway of pathologic events. It has been shown that hemodynamic cerebral autoregulatory response (measurable by CVR among other means) is disturbed by autonomic dysfunction, even in non-CNS pathologies such as familial amyloidotic polineuropathy, which is associated with peripheral autonomic failure.3 In fact, in neurodegenerative diseases, such as PD, involvement of central regulatory centers is not necessarily the only mechanism for CVR impairment, and prolonged dysautonomia of peripheral origin may affect cerebral hemodynamic autoregulation. Interestingly, recent evidence has quantified the onset of autonomic dysfunction back to ~15 years before the time of PD diagnosis.4 This long time frame would allow the development of chronic cerebrovascular injury and progression of WMHs. Regardless of the underlying pathophysiology of CVR impairment in PD, one can statistically evaluate its role in the association between WMHs and cognitive decline. The Parkinson's Progression Markers Initiative (PPMI)5 data set (http://www.ppmi-info.org), however, did not include data on CVR (because it can only be measured with a vasodilatory challenge and transcranial Doppler ultrasound) or any equivalent surrogate measure for brain hemodynamic autoregulation. Besides CVR, we still believe that dysautonomia is a primary pathologic event preceding early cognitive dysfunction in patients with PD. To further investigate whether the associations between WMH burden and cognitive decline were driven by orthostatic hypotension, we repeated the analysis separately in the subsets of PD patients that did and did not have orthostatic drop between supine and standing positions (thresholding at a value of 0, Fig. 1). For both systolic and diastolic blood pressure, the relationship between WMHs and MoCA slope (measuring future cognitive decline) was only statistically significant in the subgroups that had orthostatic hypotension (rDiastolic = −0.29, pDiastolic = 0.01, and rSystolic = −0.26, pSystolic = 0.001) and not in those that did not (rDiastolic = −0.11, pDiastolic = 0.10, and rSystolic = −0.07, pSystolic = 0.38), controlling for age, sex, and segmentation modality. This supplementary analysis further reveals that autonomic failure manifested as orthostasis is an important primary player in the onset of cognitive decline in PD. Whether or not other mediators besides WMHs (ie, CVR) also interplay in this possible causal relationship needs further investigations. In particular, future studies can be designed to assess the following mediation pathway to further clarify the pathogenesis of cognitive impairment in PD: autonomic dysregulation → cerebral dynamic dysregulation → WMHs → cognitive decline. Data used in this article were obtained from the PPMI database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org. PPMI is sponsored and partially funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including AbbVie, Avid Radiopharmaceuticals, Biogen, Bristol-Myers Squibb, Covance, GE Healthcare, Genentech, GlaxoSmithKline (GSK), Eli Lilly and Company, Lundbeck, Merck, Meso Scale Discovery (MSD), Pfizer, Piramal Imaging, Roche, Servier, and UCB (www.ppmi-info.org/fundingpartners). M.D. and D.L.C. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. M.D.: 1B, 1C, 2A, 2B, 2C, 3A, 3B S.-M.F.: 1A, 1B, 1C, 2A, 2C, 3A, 3B Y.Z.: 2C, 3B R.B.P.: 2C, 3B A.D.: 2C, 3B L.D.C.: 2C, 3B The study was approved by the institutional review board of all participating sites and written informed consent was obtained from all participants before inclusion in the study (http://www.ppmi-info.org). We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors declare that there are no conflicts of interest relevant to this work. R. Postuma receives funding from Fonds de la Recherche en Sante Quebec, Canadian Institute of Health Research, Parkinson Society of Canada, Weston-Garfield Foundation, Webster Foundation, Michael J. Fox Foundation, Roche, and has acted in a consultant or speaker capacity for Biotie, Roche, Biogen, Takeda, Jazz, Theranexus, GE, Abbvie, Jannsen, Otsuko, Boehringer, Novartis, Inception, and Phytopharmics. D.L. Collins receives funding from NSERC, CIHR, and Weston-Garfield Foundation and consults for NeuroRx Inc.