Abstract
Background: Non motor symptoms (NMS) have emerged as one of the key determinants of quality of life in people with Parkinson’s and fatigue is a common specific and distinctive NMS in PD but is often under diagnosed.Aims: In this body of work, I have attempted to explore firstly, the clinical correlates of fatigue, which may confound the characterisation of fatigue. Thereafter, the work has attempted to explore possible patho-physiological basis of fatigue in PD, addressing peripheral mechanisms such as cardiac sympathetic dysfunction within the spectrum of dysautonomia or centrally mediated mechanisms via striatal and limbic dopaminergic or serotoninergic pathways.Methods: In the first study, 135 non-depressed PD patients with an age range of 50-75 years and a clinical diagnosis of idiopathic Parkinson’s disease were studied using clinically validated scales and specifically the fatigue visual analogue scale initially to identify patients with central fatigue and those without. Collateral assessment of other confounders of fatigue chiefly depression and excessive daytime sleepiness were assessed by Non motor assessment sale (NMSS), Parkinson’s Disease Sleep Scale (PDSS), Epworth Sleepiness Scale (ESS) and Hospital anxiety and Depression Scale (HADS) In the following study, 20 patients from the above cohort with significant fatigue were further corroborated using the Parkinson fatigue Scale (PFS-16). Then 10 patients with high fatigue scores, fatigue +v patients (PFS 16 score-> 8) and 10 patients with no fatigue , fatigue -ve cases ( PFS-16 < 8) were selected to undergo cardiac 123I-meta-iodobenzylguanidine (MIBG Scanning) (using validated local protocol as well as cardiac 2-methoxy isobutyl isonitrile (MIBI scans) to study the integrity of cardiac sympathetic innervation, a sensitive marker of autonomic function. Peripheral and central mechanisms have been investigated by using combination of clinical assessments with imaging parameters of SPECT and PET scans in selected subjects. Findings were correlated with clinical measures. In the final assessment study, 40 patients were selected from the original cohort for a Positron emission tomography (PET) scan sub study (20 fatigue +v cases (PFS-16 > 8) and 20 fatigue -ve cases (PFS-16 < 8)) Patients were matched for motor severity of PD and cases with significant depression or excessive daytime sleepiness were excluded. PET imaging was performed with 18Fluoro-dopa (dopaminergic) and C-amino-4-(2-dimethylaminomethylphenylsulfanyl) benzonitrile (11)C-DASB) (serotoninergic) ligands.Results: In the first study, fatigue correlated with disease severity as measured by Hoehn and Yahr (HY) staging which stratified the condition into three categories (HY 1-2.5=Mild; HY 3=Moderate; HY 4+5 = Severe; Kruskal-Wallis test, p=0.004). There were no differences in fatigue levels between different subtypes of PD while anxiety, depression and sleepiness emerged as key clinical associations of fatigue. In the second study, a pilot exploratory work, MIBG data from 20 non-depressed PD patients (53% male, mean age (mean ± SD) of 68.75 ± 9.7 years (range: 41-88 years), mean disease duration 7 65 ± 5.5 years (range: 1-35 years) were analysed based on fatigue positive and negative cases (10 in each group) after a total assessment of 30 patients where scan was only possible in 20. The majority (51%) was at HY stage 2. Cardiac MIBG uptake was expressed as mediastinum to heart ratios at 15 min and 3 hrs (R1 and R2) and showed no difference between the fatigue versus non fatigue cases (Mean R1 of Fatigue Positive (1.6 ± 0.53) vs Mean R1 of Fatigue -ves (1.5 ± 1.37) and mean R2 of Fatigue Positives (1.58 ± 0.48 ) vs Mean R2 of Fatigue-ves (1.48 ± 0.23 )). In the third stage PET data was analysed and Fatigue + cases showed, a significantly depressed uptake of 11C-DASB binding in comparison to PD-Fatigue - cases, in caudate, putamen, ventral striatum and thalamus (p<0.001, p<0.05, p<0.01, p<0.01; Mann-Whitney-Test) and fatigue severity was inversely correlated with 11C-DASB binding. This is a novel finding never reported before. 18F-dopa uptake in the same structures was similar in the two groups using a region of interest approach, however, voxel-based statistical parametric mapping detected relatively reduced 18F-dopa uptake in caudate, thalamus and the insula in the PD-F group (p<0.001).Conclusions: Our preliminary data suggest, fatigue in PD is associated with anxiety, depression and sleepiness and appears to increase with disease severity although also evident in early-untreated phase of PD. The underlying mechanism is likely to be independent of peripheral sympathetic dysfunction as judged by cardiac sympathetic function but is associated with a severe loss of serotoninergic and dopaminergic innervation in the basal ganglia and limbic system (ventral striatum and thalamus) while sparing the raphe serotoninergic innervations. This suggests a dominant role of central serotonergic and in part, dopaminergic dysfunction in the origin of fatigue in PD.