An Investigation On Fatigue In Parkinson’s Disease:Clinical Features And Potential Mechanisms

Objective To explore the clinical features, associated factors and potentionalmechanisms of fatigue in patients with Parkinson’s disease (PD).Methods1.Evaluation of clinical features of fatigue in PD patients315PD patients who visited the department of neurology, Beijing Tiantan Hospitalfrom September2011to December2013were recruited and evaluated by FatigueSeverity Scale (FSS), Fatigue Scale-14(FS-14), scales of motor symptoms and non-motor symptoms; Linear regression analyses were performed between the score offatigue and the scores of motor symptoms and non-motor symptoms.2. Detection of pathological proteins in cerebrospinal fluid (CSF)The levels of pathological proteins, including α-Synuclein oligomer, β-amyloid (Aβ)1-42, total Tau (T-Tau) and tau phosphorylated at position of threonine181[P-tau(T181)], threonine231[P-tau (T231)], serine396[P-tau (S396)] and serine199[P-tau (S199)] in CSF in PD patients were tested; Linear correlation was performedbetween the score of fatigue and the levels of pathological proteins in CSF in fatiguegroup.3. Detection of neurotransmitters in CSFThe levels of neurotransmitters, including dopamine（DA）, and its metabolites,dihydroxy phenyl acetic acid（DOPAC）and homovanillic acid(HVA), epinephrine（NE）,serotonin(5-HT)andacetylcholine(Ach)inCSFinPDpatientsweretested;Linear correlation was performed between the score of fatigue and the levels ofneurotransmitters in CSF in fatigue group.4. Detection of iron and related proteins in CSF and serum:The levels of iron and related proteins, including, iron, ferritin (Fer), high-ferritin (H-Fer), light-ferritin (L-Fer), transferrin (Tf), transferrin receptor（TfR）, lactoferrin （Lf）,ferroportin1(FP1),divalentmetaltransport1（DMT1） andceruloplasmin（CP）in CSFandserum ofPDpatients weretested; Linearcorrelation was performedbetween the score of fatigue and the levels of neurotransmitters in CSF and serum infatigue group.5. Detection of neuroinflammatory factors in CSF and serum:The levels of neuroinflammatory factors, including hydrogen peroxide (H2O2),interleukin-1β (IL-1β), interleukin-6(IL-6), tumor necrosis factor-α (TNF-α),soluble tumor necrosis factor-α receptors-1(sTNF-αR1), total superoxide dismutase(tSOD), interferon-γ (γ-INF) and prostaglandin2(PGE2) in CSF and serum in PDpatients were tested; Linear correlation was performed between the score of fatigue andthe levels of neuroinflammatory factors in CSF and serum in fatigue group.Results1.Clinical features of fatigue in PD patients:（1）197of315(62.54%) PD patients suffer from fatigue (FSS＞4points);118of315(37.46%) PD patients don’t suffer from fatigue (FSS≤4points)；The scores oftotal fatigue and fatigue severity in fatigue group are significantly higher than those innon-fatigue group:11.00（8.00，13.00）vs.6.00(4.00，9.00) points;5.67(4.89，6.67)vs.2.17(1.56，3.44) points (P<0.05）;（2）H-Y stage and UPDRSⅢscore in fatigue group are higher than those in non-fatigue group:2.19±0.83vs.1.79±0.73stage;26.50(18.75，35.75) vs.21.00(13.88，31.00) points（P<0.05）;（3）The scores of total fatigue and fatigue severity are positively correlated to thescore of anxiety in PD patients（r=2.800,2.050，P<0.05）.2.Correlation between the score of fatigue and the levels of pathological proteinsin CSF in fatigue group：The score of fatigue severity is negatively correlated to the level of Aβ1-42in CSF infatigue group（r=-0.293，P<0.05）；The score of fatigue severity is positively correlated to the level of P-tau (T231) in CSF in fatigue group（r=0.592，P<0.05）.3. Correlation between the score of fatigue and the levels of neurotransmitters inCSF in fatigue group:There is no relationship between the score of fatigue and the levels ofneurotransmitters in CSF in fatigue group.4. Correlation between the score of fatigue and the levels of iron and relatedproteins in CSF and serum in fatigue group:(1) Correlation between the score of fatigue and iron and related proteins in CSF infatigue group: The score of fatigue severity has a positive correlation to the levels ofCP, DMT1and Lf in fatigue group（r=0.571,0.358,0.359，P＜0.05）；the score oftotal fatigue is positively correlated to the level of Tf in fatigue group（r=0.298，P＜0.05）in CSF.（2）Correlation between the score of fatigue and iron and related proteins in serumin fatigue group: The score of total fatigue has a negative correlation to the level of Tfin serum in fatigue group（r=-0.275，P＜0.05）.5. Correlation between the score of fatigue and the levels of neuroinflammatoryfactors in CSF and serum in fatigue group:（1）Correlation between the score of fatigue and the levels of neuroinflammatoryfactors in CSF in fatigue group: The score of total fatigue is positively correlated tothe level of sTNF-αR1in CSF in fatigue group（r=0.363，P＜0.05）;（2）Correlation between the score of fatigue and the levels of neuroinflammatoryfactors in serum in fatigue group: The score of fatigue severity is positively correlatedto the level of tSOD in serum in fatigue group（r=0.235，P＜0.05）.Conclusions1. PD patients have a high incidence of fatigue, and anxiety is a risk factor of fatiguein PD patients.2. Fatigue may indicate cognitive impairment due to the overloads of Aβ1-42and P-tau (T231) in the brain. 3. There are iron metabolism disorders both in serum and brain in PD patients withfatigue, which may contributes to iron deposition in brain.4. There are increased level of sTNF-α R1in CSF in PD patients with fatigue, whichmay cause the damage to the fatigue-related brain regions and produce fatigue.5. The score of fatigue severity was positively correlated with the level of tSOD inserum, indicating protective functions of neuroinflammatory factors for neuronsthrough increased oxidation resistance in early stage of PD patients with fatigue.