Tremor-Dominant in Parkinson Disease: The Relevance to Iron Metabolism and Inflammation

Abstract

Background: Tremor is one of the most predominant symptoms of patients with Parkinson disease (PD), but the underlying mechanisms for tremor relating to iron and its metabolism-related proteins and the inflammatory factors in cerebrospinal fluid (CSF) and serum have not been fully elucidated. Methods: A total of 135 PD patients were divided into a tremor-dominant (PD-TD) group ( N = 74) and a postural instability and gait difficulty-dominant (PD-PIGD) group ( N = 39) based on the ratio of mean tremor score to the mean bradykinesia/rigid score of the Unified Parkinson’s Disease Rating Scale (UPDRS) III. Age and sex-matched healthy controls were recruited ( N = 35). Demographic variables were evaluated; iron and its metabolism-related proteins and the inflammatory mediators in both CSF and serum were measured in these groups. The relevance of iron metabolism, inflammation and PD-TD were analyzed. Results: (1) The PD-TD group had significantly decreased L -ferritin, increased iron levels in CSF and increased ferritin levels in the serum compared with the PD-PIGD and control groups ( P < 0.05). (2) The PD-TD group had significantly enhanced IL-6 levels in both CSF and serum compared with the PD-PIGD and control groups ( P < 0.05). (3) In CSF, the IL-6 level was increased as the iron level was elevated in the PD-TD group ( r = 0.308, P = 0.022). In serum, the IL-6 level was increased as the ferritin level was elevated in the PD-TD group ( r = 0.410, P = 0.004). Conclusion: The interplay between disturbed iron metabolism and relevant inflammation might modulate clinical phenotypes of PD.

Biological fluid levels of iron and iron‐related proteins in Parkinson’s disease: Review and meta‐analysis

“…Finally, Genoud et al [5] included nine studies in their meta‐analysis, but the data from two of these studies, which described lower CSF iron levels in PD patients compared with controls, overlapped with data from another of the studies included. The fact that the present meta‐analysis included data from several studies [10,63,75,76,78] not included in the meta‐analysis by Genoud et al [5] should account for the differences between the two studies in the results obtained.…”

“…We performed a screening of the abstracts of all original articles, and publications in abstract form were excluded from further analysis. The initial selection included 76 studies measuring CSF, serum/plasma or urine levels of iron, ferritin, transferrin, lactoferrin, haptoglobin, and or hepcidine [6,9–83]. Table 2 summarizes the methods used for the determinations, the main results, and observations in some of these studies, including the reason for exclusion of several of these studies from the meta‐analysis.…”

Consistency and Stability of Motor Subtype Classifications in Patients With de novo Parkinson’s Disease

“…Classification of PD subtypes is based on empirical clinical observations of prominent motor symptoms. At present, the recognized PD motor subtype classifications, including tremor-dominant/indeterminate/postural instability and gait difficulty (TD/indeterminate/PIGD) put forward by Jankovic and two classifications of the TD/mixed/akinetic-rigid (AR) classification system proposed by Schiess and Kang ( Jankovic et al, 1990 ; Schiess et al, 2000 ; Kang et al, 2005 ), are widely used ( Guan et al, 2017 ; Choi et al, 2018 ; Erro et al, 2019 ; Lian et al, 2019 ; Polychronis et al, 2019 ; Ren et al,2020a,b ). Although numerous additional subtypes based on data-driven approaches have been subsequently proposed ( Graham and Sagar, 1999 ; van Rooden et al, 2010 ; Fereshtehnejad et al, 2015 ), the above three classifications occupy a dominant position in clinical practice and scientific research and have entered the conventional lexicon of clinicians.…”

Parkinson’s Disease: Can Targeting Inflammation Be an Effective Neuroprotective Strategy?

“…It should be mentioned that several groups could not find any significant difference in some of the cytokines between PD and controls. This was true for IL-6 (Lindqvist et al, 2013;Yu et al, 2014;Delgado-Alvarado et al, 2017;Starhof et al, 2018;Iwaoka et al, 2020), IFN-γ (Starhof et al, 2018;Schröder et al, 2018;Iwaoka et al, 2020), TNF-α (Lindqvist et al, 2013;Yu et al, 2014;Starhof et al, 2018), as well as for IL-1β (Starhof et al, 2018;Lian et al, 2019), IL-10 (Starhof et al, 2018;Schröder et al, 2018), and TGFβ (Starhof et al, 2018). Moreover, Iwaoka et al (2020) could not detect IL-1β and IFN-γ in the CSF of PD patients.…”

“…Second, biochemical methods have detected increased brain tissue levels of TNF-α, IL-1β, IL-6, IFN-γ, and TGF-β in the postmortem PD striatum compared to controls ( Mogi et al, 1994a , b , 1996a , 1995 , 2007 ). Third, in the CSF there are higher levels of TNF-α ( Mogi et al, 1994b ; Delgado-Alvarado et al, 2017 ; Schröder et al, 2018 ; Iwaoka et al, 2020 ), IL-1β ( Mogi et al, 1996b ; Yu et al, 2014 ; Iwaoka et al, 2020 ), IL-6 ( Mogi et al, 1996b ; Schröder et al, 2018 ; Lian et al, 2019 ), and TGF-β ( Mogi et al, 1995 ) in PD vs. controls. It should be mentioned that several groups could not find any significant difference in some of the cytokines between PD and controls.…”