Lateralisation in Parkinson disease
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Asymmetry of dopaminergic neurodegeneration and subsequent lateralisation of motor symptoms are distinctive features of Parkinson’s disease compared to other forms of neurodegenerative or symptomatic parkinsonism. Even 200 years after the first description of the disease, the underlying causes for this striking clinicopathological feature are not yet fully understood. There is increasing evidence that lateralisation of disease is due to a complex interplay of hereditary and environmental factors that are reflected not only in the concept of dominant hemispheres and handedness but also in specific susceptibilities of neuronal subpopulations within the substantia nigra. As a consequence, not only the obvious lateralisation of motor symptoms occurs but also patterns of associated non-motor signs are defined, which include cognitive functions, sleep behaviour or olfaction. Better understanding of the mechanisms contributing to lateralisation of neurodegeneration and the resulting patterns of clinical phenotypes based on bilateral post-mortem brain analyses and clinical studies focusing on right/left hemispheric symptom origin will help to develop more targeted therapeutic approaches, taking into account subtypes of PD as a heterogeneous disorder.
KeywordsParkinson’s disease Parkinsonism Asymmetry Lateralisation Dopamine Handedness Genetics
atypical Parkinsonian Syndrome
depression anxiety stress scales
definite suicidal behaviour
Diffusion Tensor Imaging
Help Advance Luxembourg’s Parkinson Research Study
left-dominant Parkinson’s disease
Lewy body dementia
late-onset Parkinson’s disease
leucine-rich repeat kinase 2
International Parkinson and Movement Disorder Society
magnetic resonance imaging
multiple system atrophy
multiple system atrophy-type parkinson
Montreal Cognitive Assessment
Parkinson’s disease with dementia
progressive supranuclear palsy
positron emission tomography
rapid eye movement
right-dominant Parkinson’s disease
substantia nigra pars compacta
single-photon-emission computed tomography
United Parkinson’s Disease Rating Scale
young-onset Parkinson’s disease
Clinical evidence of asymmetry
Parkinson’s disease (PD) is an asymmetric condition compared to other degenerative parkinsonisms, such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP) or Lewy body dementia (LBD) and a certain degree of the asymmetry is typically maintained throughout the course of the disease (Baumann et al. 2014; Counihan and Penney 1998; Cubo et al. 2010; Djaldetti et al. 2006; Fearnley and Lees 1991; Hughes et al. 1992; Kish et al. 1988). The underlying motor symptoms are primarily related to the loss of dopamine in the basal ganglia (Yagi et al. 2010), which occurs bilateral but only around 16.4% of PD patients show symmetric motor symptoms, compared to 48.3% of the MSA-P and even 52.9% of the PSP patients (Gómez-Esteban et al. 2010) corresponding to a more symmetric involvement of cortical and subcortical degeneration in MSA and PSP (Amtage et al. 2014). In a large clinical series of 1277 individuals diagnosed with PD, 46% met criteria for asymmetric disease, associated with a shorter disease duration, younger age at symptomatic onset, asymmetrical initial symptom onset, hand dominance and a positive self-reported family history of “other” neurodegenerative disorders. Hand dominance was related to the side of asymmetric disease such that left-handed individuals tended to have more severe disease on the left side of the body (Uitti et al. 2005). In patients with MSA-P, putaminal atrophy was frequently observed (14/27 cases, 51.9%) and was most commonly found in the unilateral putamen (13/14 cases). Marked signal hypointensity was observed in 12 patients with MSA-P (44.4%). No patients with idiopathic PD or healthy controls showed putaminal atrophy or marked signal hypointensity. Quantitatively measured putaminal width, phase-shift values and the ratio of mean phase-shift values for the dominant and nondominant sides were significantly different between the MSA-P group and the idiopathic PD and healthy control groups (p < 0.001) (Hwang et al. 2015). However, a few cases of MSA-P can initially present with marked asymmetric parkinsonism and rigid dystonic limb posturing leading to a diagnosis of corticobasal syndrome at onset (Batla et al. 2013). Asymmetry of clinical features is a common finding in PD and many patients have not only unilateral motor symptoms but also non-motor deficits (Djaldetti et al. 2006; Tang et al. 2010) at the time of onset, while asymmetry may become less prominent over the course of the disease (Nandhagopal et al. 2009). In early PD, the lateralisation of brain activity during unilateral movement is significantly reduced, the disruption of the lateralised brain activity pattern may be a reason underlying some motor deficits, like mirror movements or impaired bilateral motor coordination (Wu et al. 2015). The motor asymmetry observed in PD may serve as a clinical parameter to differentiate PD from other parkinsonian syndromes (Brooks and Pavese 2009). Indeed, clinical asymmetry in PD can be even found at later stages of the disease, with more marked extrapyramidal involvement on the body side first affected (Kempster et al. 1989).
Also, in the recently established Parkinson cohort in Luxembourg (Hipp 2015), the vast majority of the recruited PD patients had initially unilateral symptoms. Out of 352 patients with PD or PD with dementia (PDD), 87.5% had as initial symptom unilateral (left or right sided) tremor, 69.7% unilateral rigidity and 66.4% unilateral bradykinesia. Absolute numbers were much lower for the atypical parkinsonian syndromes (aPS) due to their rarity but also showed a trend towards a unilateral initiation of symptoms. After a mean disease duration of 9.08 ± 7.37 years, tremor was asymmetric in 84.3% of the patients with aPS and rigidity and bradykinesia asymmetric in 58.6% and 54.7% of the patients, respectively. This trend was more pronounced in aPS, where after a mean disease duration of 5.59 ± 5.71 years, asymmetric symptoms are only 41% of the patients for bradykinesia and 55.2% for rigidity (but 72.9% for tremor). This underlines that idiopathic PD has typically a unilateral disease onset but it tends to become symmetric after several years of disease duration, especially in bradykinesia and rigidity. Compared to healthy individuals, patients with PD usually exhibit greater asymmetry while performing tasks requiring postural control (Beretta et al. 2015).
The typical asymmetry of clinical symptoms at disease onset is observed not only in the common sporadic form of PD but also in monogenic forms of the disease (Djaldetti et al. 2006; Riederer and Sian-Hülsmann 2012), although the mechanism of the initial unilaterality of symptom appearance is poorly understood (Martinu et al. 2014). There is only sparse information about whether such unilaterality is genetically encoded or whether it is acquired and related to side differences in vulnerability of the degenerating neurons (Djaldetti et al. 2006). Many hereditary types of PD appear to be typical in terms of the initial unilaterality and subsequent bilateral with dominant side phenotype (Doherty et al. 2013; Houlden and Singleton 2012; Kiely et al. 2015; Neumann et al. 2009; Schiesling et al. 2008). Indeed, the asymmetry of radioligand uptake in PD associated with glucocerebrosidase (GBA) or leucine-rich repeat kinase 2 (LRRK2) mutations supports that also genetic forms of PD present with asymmetry and indicates that genetic or environmental factors may be associated with dopaminergic neuron loss (McNeill et al. 2013). Asymmetrical onset was also reported in the majority of patients with Parkin mutations (Lohmann et al. 2003a, b).
Handedness and side of motor onset
It has been suggested that the side of onset of initial motor symptoms of PD and the dominant hand are independently related (Amick et al. 2006; Jellinger 2014; Yust-Katz et al. 2008). PD symptoms emerge more often on the dominant-hand side and the dominant side of symptoms is usually in accordance with handedness (Barrett et al. 2011; Shi et al. 2014; van der Hoorn et al. 2012).
In this context, PD symptoms emerge more often on the dominant hand side, probably due to an increased nigrostriatal dopamine turnover in the dominant hemisphere supported by in vivo measurements with PET, even suggesting to find asymmetric dopamine cell count (Klawans 1972; de la Fuente-Fernández et al. 2000; van der Hoorn et al. 2012).
Tremor, bradykinesia and akinesia are the cardinal features of PD and it appears that lateralisation of motor symptoms may be related to non-motor symptoms. Here, it has been initially reported that right-sided onset of tremor (and other motor dysfunctions) is related to a better cognitive function compared to left-sided onset (Direnfeld et al. 1984; Tomer et al. 1993). Recent studies found that PD patients exhibiting a more marked left hemisphere motor dysfunction exhibited greater cognitive impairment (Hanna-Pladdy et al. 2015). Vice versa left-sided onset and left-handedness were related to a more benign disease course (Munhoz et al. 2013). The degree of motor dysfunction does not determine the severity of cognitive impairment; the latter appears to depend on the basal dopamine levels. Interestingly, in the healthy brain, the left hemisphere boosts a greater striatal dopamine content than the right; thus, the brain appears to present with an uneven distribution of dopamine content (Brichta and Greengard 2014). This may confer susceptibility of the nigro-striatal tract to degenerate, particular in the presence of a trigger factor(s) responsible for causing the disease. Indeed, a recent study showed that an increased dopamine metabolism is critically related to oxidation, lysosomal dysfunction and finally neurodegeneration and even explains the species-specific degeneration of dopaminergic neurons from humans with PD (Burbulla et al. 2017)
Side of motor onset and non-motor symptoms
Interestingly, Amick et al. (2006) found that the side of motor onset is related to differential patterns of cognitive impairment. PD patients with right-side motor symptom predominance present more difficulties in tasks of language and verbal memory, whereas those with left-side motor symptoms present more difficulties in visuospatial tasks, indicating that the side of clinical motor predominance influences cognition suggesting that cognitive differences between subgroups of lateralised PD patients may appear in more advanced disease stages (Poletti et al. 2013; Pellicano et al. 2015). Recent data suggest that the onset of asymmetric motor symptoms in PD may be associated with hemisphere-specific memory decline and lateralised grey matter loss, particularly in left-dominant PD (LPD). This underscores the importance of classifying PD subgroups based on the side of motor symptom onset for clinical care and research to optimize cognitive outcomes (Riederer and Sian-Hülsmann 2012; Lee et al. 2015). Patients with motor onset on their dominant side show significantly fewer motor deficits than non-dominant-side ones, suggesting that the first group has a greater neural reserve allowing them to better cope with PD-related changes (i.e., fewer motor deficits despite similar dopamine reduction), i.e., better motor compensation (Ham et al. 2015). Other studies support a direct involvement of the asymmetry of gait in the development of freezing of gait in PD (Frazzitta et al. 2013).
Schendan et al. (2009) linked side of motor symptom onset to visuospatial cognitive abilities that depend upon the contralateral posterior temporoparietal junction and highlighted that side of onset can predict visuospatial impairments. Using normative neuroimaging and neuropsychology, an individual diagnosed with PD had been described, finding striking striatal asymmetry followed secondarily by cortical thickness asymmetry and possible frontal white matter asymmetry. This decline and variability in visual working memory could be linked to ongoing atrophy of his right caudate nucleus (Tanner et al. 2017). It has been hypothesized that inhibitory control relies upon a right-lateralized pathway and it was tested whether LPD patients suffered from a more severe deficit in this key executive function than right-dominant PD (RPD) patients. In an assessment of both proactive and reactive inhibition in 20 LPD, 20 RPD and 20 age-matched healthy subjects, PD patients were significantly more impaired in both forms of inhibitory control than healthy subjects. However, there were no differences either in reactive or proactive inhibition between LPD and RPD patients. All in all, these data support the idea that brain regions affected by PD play a fundamental role in subserving inhibitory function but do not sustain the hypothesis according to which this executive function is predominantly or solely computed by the brain regions of the right hemisphere (Mirabella et al. 2017). Compromised executive function in LPD and greater anxiety on the DASS Anxiety scales and lower magical ideation were separated by Modestino et al. (2017). However, this increased anxiety—in contrast to Foster et al. (2008)—could not account for the poorer performance on the DSB for left-onset PD (Modestino et al. 2017). PD patients show a higher anxiety level than controls. In LPD, apathy but not anxiety was associated with performance on non-verbally mediated executive function and visuospatial measures, whereas, in RPD, anxiety but not apathy correlated with performance on verbally mediated task (Bogdanova and Cronin-Golomb 2012). Motor-symptom laterality could affect feedback-based associative learning in PD, with left-onset medication-naive patients being selectively impaired. Dysfunction in the right dorsal rostral putamen may underlie the observed deficit in associative learning in patients with left-sided onset (Huang et al. 2017).
The first results of the HELP-PD cohort in Luxembourg (Hipp 2015) seem to provide hints that right-handed PD and PDD patients with contralateral onset of their motor symptoms (on their non-dominant body side; N = 86) tend to have a slightly higher MDS-UPDRS-III of 30.84 ± 15.04 and more motor complications (MDS-UPDRS-IV 2.20 ± 3.45) but having less repercussions on activities of daily life with an MDS-UPDRS-I of 9.64 ± 7.16 and MDS-UPDRS-II of 10.54 ± 7.69, compared to patients with right-handed motor onset of their symptoms (N = 77) with MDS-UPDRS-I, II, III and IV scores of 10.73 ± 6.79, 12.38 ± 8.75, 29.13 ± 17.94 and 1.87 ± 3.10, respectively). The cognitive function measured with the MOCA score was slightly better in right-handed patients with a disease onset on their non-dominant side (24.91 ± 3.99 vs. 24.26 ± 3.85). The difference was even greater in right-handed patients with predominant right hemispheric symptoms (N = 112) compared to those having motor symptoms predominantly from the left hemisphere (N = 132; MDS-UPDRS-III 33.89 ± 15.08 vs 30.70 ± 18.76). Cognitive function seems to be similar (MOCA 24.31 ± 4.28 vs 24.36 ± 4.55) between both groups of right-handed patients. Of course, these trends need still to be verified after completion of patient recruitment of the HELP-PD cohort but seem to indicate that the non-dominant right hemisphere is more vulnerable in right-handed patients. On the other hand, in early PD, the side of onset of motor symptoms did not seem to influence neuropsychiatric and cognitive symptoms (Pellicano et al. 2015), which was debated by Erro et al. (2015).
Early disease onset, left-handedness and left-side onset are associated with long disease and ambulatory PD survival (Munhoz et al. 2013; Modestino et al. 2017) but also increased frequency of REM sleep behavior disorder (Baumann et al. 2014), while left motor dysfunction and smaller right substantia nigra (SN) volume were associated with poorer spatial memory (Foster et al. 2008). A nationwide longitudinal and multicenter study showed that right-onset PD had higher psychosis rating scales over time compared with left-onset PD but no significant differences were observed for other non-motor symptoms (Cubo et al. 2010). Olfactory dysfunction in early PD is robust, typically of the same general magnitude on both sides and uninfluenced by anti-Parkinson medication (Doty et al. 1992), whereas according to others, there is more olfactory sensitivity contralateral to the more affected side of the body (Zucco et al. 2001) and hemihyposmia was reported in a case of hemiparkinsonism (Heckmann et al. 2004). This appears of interest, because olfactory dysfunction is a very early symptom in PD in contrast to other forms of parkinsonism (Attems et al. 2014; Wenning et al. 1995). This is suggested to result from a complex network dysfunction that exceeds the pathology of the olfactory bulb and mesolimbic cortices (Attems et al. 2014; Moessnang et al. 2011). Rey et al. (2016) recently demonstrated that pathology induced by unilateral injection of human or mouse wild-type α-synuclein (αSyn) pre-formed fibrils (PFFs), designated huPFFs or mPFFs, respectively, into the olfactory bulb (OB) of 3-month-old wild-type (WT) mice can propagate sequentially over multiple synaptic relays, reaching numerous ipsi- and contralateral brain regions after 12 months, including brain stem areas (e.g., a few aggregates in the SN, locus coeruleus (LC) and raphe nucleus (RN)). The spreading of α-syn aggregates was coupled to progressive deficits in olfaction. Of particular interest is the notion that in a meta-analysis both the left and the right OB volume were significantly smaller in PD than in healthy controls (Li et al. 2016). However, right-sided PD performed worse with the left nostril, while no nostril-related differences were observed in controls (Zucco et al. 2015).
In agreement with Hobson (2012), this points to the conclusion that asymmetry in PD results from a greater susceptibility of SN in one hemisphere. Another possibility would be an initiation of spreading pathology that starts on one side and subsequently involves the other side (Hobson 2012). For example, presynaptic modulation of olfactory sensory neurons by local interneurons as a mechanism for gain control, cell class specific effects of serotonergic centrifugal neurons on olfactory processing or the integration of intrinsic and extrinsic neuromodulation are important control mechanisms of olfactory network dynamics (Lizbinski and Dacks 2018; Sun et al. 2017). In addition, genetic alterations may contribute to the asymmetry as seen in PD.
Notably, the studies of Park et al. (2018) demonstrated that in patients with PD plus MCI the olfactory dysfunction was more prominent compared to PD without cognitive disturbances, pointing to more extensive or multiple pathologies underlying olfaction in patients with PD plus MCI (Park et al. 2018; Lizbinski and Dacks 2018).
In the gastrointestinal tract left-sided vagal innervation of the stomach/cardiac and right-sided vagal innervation of the small intestine and proximal part of the colon has been described (Standring and Gray 2008). However, there is so far no evidence that these asymmetries contribute to the pathology of PD. In the experimental studies of Pan-Montojo et al. (2010) using systemic applications of rotenone into the gastrointestinal tract, parkinsonism was shown to be bilateral. Therefore, it is of importance to design experimental studies with the focus on asymmetries.
Histopathological evidence for asymmetric dopaminergic cell loss in brain
In sporadic PD, the essential neuropathology is considerable neuronal loss in the DAergic substantia nigra compacta (SNc) associated with Lewy body (LB)/αSynuclein pathology involving the central and peripheral nervous system and multiple organs (Beach et al. 2010; Jellinger 2012, 2014). Stereological analyses of the number of SN neurons, performed only on one side (unilaterally) found significant loss of pigmented (− 28.3%) and TH+ (− 36.2%) neurons in older versus younger healthy subjects but up to 70-80% cell loss with significant atrophy of pigmented nigral neurons in end-stage PD patients (Rudow et al. 2008), while others reported reduction of SN neurons in PD by 66% compared to controls (Pakkenberg et al. 1991). Earlier studies reported midbrain DAergic neuron loss in PD brains of around 50% of healthy controls, in area A 8 and 9 (− 61%) and ventral tegmental area A 10 (− 48%) (German et al. 1989). Cell loss in the SN is not uniform, preferentially affecting regions with synaptic connection to the putamen (Hassler 1938). Thus, the degree of asymmetry in the regions of the SN may be greater than is suggested by whole nigral cell counts. The most severe depletion involves the nigrosome 1, located in the caudal and mediolateral tier of SNc, projecting to the striatum and spreading along a caudo-rostral, latero-medial and ventro-dorsal progression (Damier et al. 1999). This temporo-spatial disorder corresponds to a somatotopic pattern of DAergic terminal loss in the dorsal and caudal putamen, with later involvement of the ventral putamen and caudate nucleus (Kish et al. 1988). Recent 7T MRI studies allowed for the visualization of the nigrosome 1 as a hyperintensive signal in the SNc of healthy subjects (“swallow tail sign”) and its absence in PD patients, probably because of the loss of melanized neurons and the increase of iron deposition in degenerated SN (Lehéricy et al. 2014).
A clinico-pathological study of 21 PD cases (age at onset 39–73; mean 57 ±9 years; duration 4–23, mean 13.7 ± 8 years) showed considerable asymmetry of the mean nigral neuronal count with a 25% reduction in the SN contralateral to the initially more affected body side, thus providing pathological confirmation for the predominantly unilateral motor manifestation (Kempster et al. 1989). To the best of our knowledge, no other bilateral numeric SN cell counts are available. Further post mortem studies provided support for the occurrence of DA asymmetry (Glick et al. 1982; Toga and Thompson 2003). The right hemisphere appears to have lower levels of DA compared to the left, which may in turn confer susceptibility to dopaminergic degeneration. Alternatively, this neurochemical lateralisation may compromise the plasticity of the right hemisphere in the disease process in PD. Eventually, the progressive neurodegeneration of the SN leads to the manifestation of motor symptoms characteristic of the illness. Data on asymmetry of non-dopaminergic systems in PD, to the best of our knowledge, are currently not available.
Given the extent of preclinical dopaminergic denervation (Tissingh et al. 1998), it is conceivable that compensatory changes extend also beyond the nigrostriatal portion of the motor circuit. Patients with clinically asymmetric PD represent a valuable model to study compensatory reorganisation within the motor system since functional changes that prevent motor symptom progression are likely to be more evident on the less affected side. A previous [18F]-fluorodeoxyglucose PET study provided little evidence that this might be the case. Asymmetric patients had an equally abnormal metabolic pattern in cortex and subcortical structures of both hemispheres (except within the putamen) (Tang et al. 2010). However, an apparent absence of metabolic asymmetry in the sensorimotor cortex, a major output of basal ganglia–cortical loops, could reflect insufficient sensitivity of metabolic measures. Increased motor cortical plasticity on the less affected side is consistent with a functional reorganisation of the sensorimotor cortex and may represent a compensatory change that contributes to delaying onset of clinical symptoms. Alternatively, it may reflect a maladaptive plasticity that provokes symptom onset. Plasticity deteriorates as the symptoms progress, as seen on the more affected side (Kojovic et al. 2012).
The motor symptoms are exhibited after a marked loss of the nigral neurons resulting in a consequent depletion of the striatal dopamine especially at the side of disease onset. Thus, the ability of the nigro-striatal motor pathway to compensate in spite of the marked cell loss illustrates the remarkable robustness of the system (Bernheimer et al. 1973). Perhaps, the preclinical phase may illustrate a gradual rate of destruction of nigral dopaminergic neurons, preferring one side at the very begin of disease onset. Compensation is suggested to show a higher degree on the more affected side. Laterality of nigrosome 1 was in concordance with clinical laterality. Unilateral symptomatology in PD corresponds to neuronal nigrostriatal degeneration in the contralateral hemisphere; the abnormality of nigrosome 2 can be detected at 3T and 7T MRI with an accuracy of 94.6% (Noh et al. 2015). In PD, the lateral surface of the SN presents an undulated aspect, which predominates in the more severely affected hemisphere (contralateral to the more severe clinical symptoms (Kwon et al. 2012; Lehéricy et al. 2014). Striatal DA loss significantly correlates with loss of DAergic SN neurons (Bernheimer et al. 1973) but neither αSyn nor ß-amyloid (Aβ) deposition (Colloby et al. 2012). Dopamine transporter (DAT) immunoreactivity in the striatum is inversely correlated with the total αSyn burden but not with the Lewy body counts nor the SN, which supports the concept of synaptic dysfunction or impairment of axonal transport of αSyn aggregations (Kovacs et al. 2008). Whether the distribution of LB, as an index of abnormal α-syn deposition and pathological hallmarks of PD, may influence the lateralisation of PD is unknown (Djaldetti et al. 2006).
DA markers in dorsal putamen show mild (around 10%) loss one year after clinical diagnosis but 50–90% TH+ neuron loss at 4 years, loss of melanized SN neurons lagging behind the loss of striatal DA markers (Kordower et al. 2013). However, recent SPECT studies indicated that degeneration of the dopaminergic system is not total, even after many years of illness, the loss being more prominent in the putamen than in the caudate nucleus (Djaldetti et al. 2011). Around 12% nigral cell loss was already observed before αSyn aggregation and increased to 46% at Braak Lewy stages 3 and 4 (Dijkstra et al. 2014).
Unilateral patients display 20% of abnormal αSyn deposits in the C7 paravertebral spinal regions contralateral to the clinically more affected (motor) side, 60% in both sides and 20% in the non-affected side (Donadio et al. 2017),
The striatal DA transporter (DAT) binding in 5 cases of LB disorders (2 PD, 3 DLB) moderately correlated with the asymmetry of DAergic degeneration in the SNc, based on the number of neuromelanin-containing neurons (r = 0.76; p = 0.028) (Kraemmer et al. 2014). DAT imaging in 14 autopsy-confirmed cases of PD (n = 8) and MSA (n = 6), demonstrated that mean overall striatal DAT binding was reduced by 52% in PD and 53% in MSA, with a greater trend for asymmetry of striatal binding in MSA compared to PD (23 ± 15 vs 10.5 ± 7%, respectively; p = 0.71), with 3 MSA patients showing more asymmetry of striatal DAT binding than any PD patient (Perju-Dumbrava et al. 2012), whereas others found less asymmetric striatal ß-CIT binding in 26 clinical MSA compared with 157 PD patients (Varrone et al. 2001) and more asymmetry of striatal β-CIT binding in clinical cases of PD than in MSA (Knudsen et al. 2004).
The majority of clinico-pathological studies of PD staging protocols and morphological reviews (Braak et al. 2003; Braak and Del Tredici 2008; Halliday and Murphy 2010; Jellinger 2012) as well as recent MRI and PET studies on basal ganglia and nigrostriatal function in PD (Péran et al. 2010; Perlmutter and Norris 2014; Rolinski et al. 2016) did not consider lateralisation or asymmetry of the motor symptoms and, to the best of our knowledge, there are only few such studies considering clinical and morphological lateralisation. Evidence for an asymmetry of this neurodegenerative process was first provided by Barolin et al. (1964), who reported a reduction in striatal DA content contralateral to the most affected body side in a case with PD. Among 20 neuropathologically and biochemically studied cases of PD, five (aged 66–82; mean 75 years; disease duration 4–12; mean 5.5 years), showed asymmetrical clinical symptoms, which were associated with different severities of neuronal loss in various parts of the SN, although side differences of the dopaminergic striatal system were not measured (Bernheimer et al. 1973). The same holds true for recent MRI studies of the SN in PD (Prasad et al. 2018).
Neuroimaging-based evidence for asymmetric dopaminergic neurodegeneration
SPECT and PET studies of fluorine-18-labelled fluorodopa (18 F-DOPA) assessing the integrity of the presynaptic nigrostriatal system show reduced tracer uptake in the posterior putamen contralateral to the predominantly affected side as an almost pathognomic sign for PD (Leenders et al. 1990; Rinne et al. 1993; Snow et al. 1993; Bohnen et al. 2006; Kaasinen 2015). Shape analysis in de novo PD patients using DAT SPECT suggested a progressive medial-to-lateral involvement of the putamen that paralleled an asymmetric-to-bilateral distribution of DAT depletion (Caligiuri et al. 2016). Asymmetric scans are observed not only in early forms with mild symptoms but also in prodromal asymptomatic cases who developed parkinsonian symptoms years after detection by imaging (Laihinen et al. 2000). PET studies in young (YOPD) and late onset PD (LOPD) cases showed that the caudate/anterior putamen ratios were significantly higher in YOPD than that in the LOPD (p = 0.03 contralateral to the most affected side of the body and p = 0.004 ipsilateral), which was supported by significantly inverse correlations between age of onset and caudate/anterior putamen ratios (r = − 0.428, p < 0.001 for the contralateral and r = − 0.576, p < 0.001 for the ipsilateral). Sub-regional DAT binding in the caudate ipsilateral to affected limbs was significantly correlated with age, while DAT bindings in putamen were significantly inversely correlated with disease duration and UPDRS motor scores (Liu et al. 2015). Patients with unilateral onset increase contralateral to the most clinically affected side, i.e., in the most damaged side (Kumar and Mandal 2003).
FDG-PET studies demonstrated inverse asymmetry of basal ganglia glucose metabolism in PD patients (Dethy et al. 1998) and 18-FDOPA PET showed biochemical asymmetry in the caudate and putamen in early PD, correlating with asymmetry of motor symptoms (Kumakura et al. 2006). This pattern of asymmetry generally remains unaltered during disease progression (Benamer et al. 2000).
PET studies showed lateralisation of DAergic function in that right caudate 18F-DOPA uptake selectively covariated with certain memory performance tasks and left putamen 18F-DOPA uptake with performance on verbal working memory tests, indicating that subcortical structures may be important mediators of lateralised hemispheral functions (Cheesman et al. 2005). 18F-DOPA uptake studies showed that in PD but not in controls, reaction time is inversely related to the levels of DA in the left lateral orbitofrontal cortex (Marinelli et al. 2015).
The lateralisation of brain activity pattern during right-hand movement is weakened, and the left dominance of lateralisation is reduced but shows a tendency to bilateral dominance; this supports a neuroprotective effect of enhanced physical activity by handedness on the contralateral motor cortex (Kim et al. 2014). On the other hand, β-CIT SPECT imaging demonstrated bilateral loss of striatal DAT by approximately 53% contralateral and 38% ipsilateral to the clinically symptomatic side in hemi-PD patients (Marek et al. 1996). However, the preponderance of reduced left putaminal DAT availability strengthens the clinical observation of a greater proportion of right-handed PD patients with predominantly right-sided motor signs and argues against a randomly distributed asymmetric vulnerability of SN DAergic neurons (Erro et al. 2013; Hoshiyama et al. 2015. The fact that right-handed PD patients had predominant right-sided motor symptoms and left-sided DA deficits, whereas the effect was opposite in left-handed patients (p = 0.005 and 0.028, respectively), suggested that the side of DAergic deficits in PD are not random but are directed by brain lateralisation (Kaasinen 2015). A meta-analysis previously provided evidence of the association between the predominant side of PD symptoms and hand dominance (van der Hoorn et al. 2012). A subgroup of right-handed PD patients with more severe and predominant ipsilateral DAT decline suggests that asymmetry of DAergic denervation and motor dysfunction in PD cannot be fully explained by hemispheric dominance alone but that other factors may also be involved, that, however, needs further elucidation (Scherfler et al. 2012). Other recent functional MRI studies in early PD patients showed the lateralisation of brain activity during unilateral right-hand movement to be weakened. The left dominance of lateralisation was significantly reduced but showed a tendency to bilateral dominance (Wu et al. 2016). Motor asymmetry and SN volume changes have been shown to be related to spatial response performance in PD (Foster et al. 2009).
Recent 18F-flortaucipir PET studies in PD patients have consistently shown no increased tau binding in the basal ganglia or in the cerebral cortex (Gomperts et al. 2016; Hansen et al. 2016; Lee et al. 2018; Schonhaut et al. 2017). PD patients exhibited approximately 13% lower 18F-flortaucipir tau-binding in the substantia nigra compared to controls (Hansen et al. 2016; Schonhaut et al. 2017), due to off-target binding of 18F-flortaucipir to neuromelanin pigment, which normally exists in the substantia nigra and is lost in PD (Lowe et al. 2016; Marquié et al. 2015). Reduced 18F-flortaucipir tau-binding was more prominent in the lateral part of the substantia nigra than in the medial part. However, nigral 18F-flortaucipir tau-binding did not correlate with the motor severity of PD and did not reflect clinical asymmetry (Hansen et al. 2016).
Modern MRI methods (transverse relaxation mapping and DTI) demonstrated significant differences between the symptomatic and non-symptomatic hemispheres, in particular fractional anisotropy and mean diffusivity in the putamen in early-onset PD, supporting the hypothesis of asymmetric neurodegeneration in the bilateral nigrostriatal pathways emerging already in the early stage of the disease (Wang et al. 2015). Functional MRI investigation of the lateralisation brain activity patterns during performance of unilateral movement in drug-naive PD patients with only right hemiparkinson symptoms showed decreased activity in the left putamen and left supplementary motor area but increased activity in the right primary motor and premotor cortex, left post-central gyrus and bilateral cerebellum. The connectivity from the left putamen to motor cortex regions and cerebellum was decreased, while interactions between the cortical motor regions, cerebellar and right putamen were increased. This study demonstrated that in early PD, the lateralisation of brain activity during unilateral movement is significantly reduced. The dysfunction of the striato-cortical circuit, decreased transcallosal inhibition and compensatory efforts from cortical motor regions, cerebellum and the less affected striatum are likely reasons contributing to the reduced motor lateralisation (Wu et al. 2015). Volumetric analysis of SN volume asymmetry showed poor agreement with clinical asymmetry in 60 patients with PD (Durmaz et al. 2016), while iron-related MRI contrast asymmetry in SN was higher in PD than in controls (Gorell et al. 1995). More recent MRI studies found a significant correlation between asymmetric motor features in PD and T1ρ relaxation time in SN, which is sensitive to cellular changes and the presence of iron (Nestrasil et al. 2010). Recent MRI studies of the posterior SN revealed a lateral asymmetry and spatial difference of iron deposition in the more affected hemibrains than in controls (p < 0.05) (Azuma et al. 2016). Of interest is a finding of Xu et al. (2008) showing that there is a hemispheric asymmetry of iron already in healthy individuals with a higher concentration of iron in the mid brain of the left hemisphere.
Significant asymmetry was observed in the fractional anisotropy and apparent diffusion coefficient at the rostral SN of PD subjects and significant correlation was rated with UPDRS (Prakash et al. 2012). The right SN had increased fractional anisotropy compared to the left one (Lenfeldt et al. 2015). Proton MRI spectroscopy for monitoring pathologic changes in SN and globus pallidus in early PD showed that the changes in the globus pallidus are more pronounced on the side affected at the onset of PD, which may contribute to the development of asymmetric symptoms and signs; the N-acetyl aspartate (NAA)-to-creatine ratio for the initially symptomatic side of the SN was negatively correlated with the (UPDRS) score (r = − 0.279; p = 0.039) (Wu et al. 2016). Another protein MR spectroscopy study of SN metabolites in PD revealed significant differences in NAA/Creatine, NAA/Cholin, NAA/(Cholin + Creatin) between the ipsi- and the contralateral SN of affected extremity (p < 0.05), indicating metabolic differences (Zhou et al. 2014). A longitudinal high-field (1) H-MR spectroscopy imaging study of the NAA to creatine ratio showed a higher side-to-side asymmetry in the PD group (16.7%) vs. healthy controls (1.6%, p = 0.0024) (Seraji-Bozorgzad et al. 2015).
Levodopa has been shown to provide additional DAergic input, improving movements for the more severely affected side; This suggests that the impact of reduced DA in the cortico-striatal system and the action of DA is not symmetrical (Martinu et al. 2014; Androulidakis et al. 2007)
Cortical degeneration in PD differs between cerebral hemispheres and recent T1-weighted brain MRI findings suggest a pattern of early left and late right hemispheral cortical atrophy in left frontal regions, especially left insula and OB, suggesting early susceptibility of the left hemisphere. This pattern was not influenced by the degree of motor symptom asymmetry (Claassen et al. 2016). Side of onset may influence the pattern of cerebral atrophy in PD. Indeed, left-sided onset PD has a grey matter atrophy in the insula, putamen, anterior cingulate, fronto-temporal cortex and right caudate, while the right side onset PD group showed atrophy at the anterior cingulate, insula, fronto-temporal and occipital cortex (Santos et al. 2016). However, a recent meta-analysis comprising 159 voxel-based morphometry publications (4469 patients, 4307 controls), in contrast to increased left-hemisphere vulnerability in aging and neurodegeneration, showed no consistent pattern in PD (Minkova et al. 2017). Recent magnetoencephalographic studies showed a direct relationship between symptom asymmetry and the laterality of neuronal activity during movement in PD patients, suggesting that left-dominant patients have a different oscillatory pattern than right-dominant patients (Heinrichs-Graham et al. 2017). In agreement with PET-studies reported above, echogenicity as measured with transcranial ultrasound was significantly increased contralateral to the side with more severe symptoms (Berg et al. 2001)
Environmental toxins and laterality in PD
As described in detail (Riederer and Sian-Hülsmann 2012), the vast majority of environmental toxins cause bilateral parkinsonism when applied systematically. This holds true for viral infections, which lesion the SN (Jung et al. 2007) or precipitate parkinsonism after intra-uterine exposure to the influenza virus (Mattock et al. 1988). Studies on post-encephalitic parkinsonism also provide no evidence for unilateral onset of the disease (Espay and Henderson 2011; Dale et al. 2004; Picard et al. 1996). Furthermore, patients with HIV infection, respective AIDS, often exhibit symmetric parkinsonian motor features.
Sporadic parkinsonism can be triggered by chemicals, like those inhibiting the respiratory chain activity, carbon monoxide and various metals. In all these cases, parkinsonism is symmetrical with rare exceptions (Bortolozzi et al. 2003; Rissanen et al. 2010; Riederer and Sian-Hülsmann 2012).
Lateralisation and animal models in Parkinson’s disease
Neurotoxins such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are used in animal models for studying pathogenesis and therapeutic strategies in PD. A limitation of neurotoxic models is the unwanted side effect of a toxin (Casey 1997).
As described in detail (Riederer and Sian-Hülsmann 2012; Zheng and Poon 2017), environmental toxins in both animals and humans cause bilateral parkinsonism with some rare exceptions. Therefore, unilaterality especially in the early phase of PD is of particular interest for studies into its pathological basis. For example, asymmetric degeneration of the nigro-striatal dopaminergic pathway results in functional asynchrony between the intact and the 6-OHDA-lesioned caudate-putamen (Monnot et al. 2017).
Therefore, a commonly used animal model employs unilateral injection of 6-OHDA into the SN of rodents. This results in the selective destruction of DAergic neurons, resulting in asymmetric motor deficit similar to that in PD. The side of motor symptoms is contralateral to the side of 6-OHDA injection. Interestingly, the area (SN or striatum or medial forebrain bundles) into which the 6-OHDA is injected determines or predicts the degree of neuronal destruction and thus motor features. Boix et al. (2015) found that partial lesions induced by 6-OHDA injection into the medial forebrain of mice, produced a significant nigrostriatal lesion and behavioral asymmetry. The motor lateralisation can be effectively gauged using the corridor test (Grealish et al. 2010). Recent stereological quantitative analysis of TH-positive dopamine neuron numbers in a rat 6-OHDA nigral lesion model of PD established the relationship between behavioral asymmetry and dopamine neuron loss in the lesioned side (Fabricius et al. 2017). No significant differences were demonstrated in the absolute MRI values between 6-OHDA animals and controls; however, 6-OHDA animals showed significant striatal asymmetry for all MRI parameters in contrast to controls. These PD-related asymmetry ratios might be the result of counteracting changes in both intact and affected striatum and allowed to diagnose PD lesions. As lateralisation is known to occur also in PD patients and might be expected in transgenic PD models as well, MR-derived asymmetry ratios in the striatum might be a useful tool for in vivo phenotyping of animal models of PD (Van Camp et al. 2010). In unilateral 6-OHDA rats treated with a single intraperitoneal injection of l-dopa, asymmetric degeneration of the nigrostriatal dopamine pathway may result in functional asynchrony between the intact and lesioned caudate-putamen and increased interhemispheric synchrony between sensorimotor cortices (Monnot et al. 2017).
Mice were unilaterally infused with either vehicle or rotenone (2 μg/site) in both the medial forebrain bundle and the SN. The forelimb asymmetry (cylinder) test indicated a significant decrease in use of the contralateral forelimb in lesioned animals as compared to the sham group. Densitometric analysis revealed a significant depletion of TH immunofluorescence within the ipsilateral striatum and substantia nigra of lesioned animals. Moreover, a significant bilateral increase in α-syn immunofluorescence was found in the SN of lesioned mice, as compared to control animals (Carriere et al. 2017). As such, the notion is of interest; that systemic gastrointestinal application of rotenone in mice caused bilateral parkinsonism (Pan-Montojo et al. 2010).
Chronic MPTP administration in monkeys results in the progressive degeneration of the nigral neurons thus mirroring a major pathology of PD. The motor disturbances are exhibited contralateral to the unilateral MPTP induced lesion (Schneider et al. 1982), thus supporting the notion that asymmetric lesions in the basal ganglia produce motor lateralisation demonstrated in PD. Perhaps, as the disease progresses the lesions spread to the other unaffected hemisphere and thus losing the motor laterality.
Genetics and lateralisation in PD
As lateralisation of brain structures and motor behaviour has been already described in human foetuses as early as 10 weeks after gestation, with right-handedness observed in 85%, similar to the adult rate of right-handedness, this clearly indicates the presence of asymmetric genetic developmental programmes (Hepper et al. 1998). As the basis for this neuropsychological lateralisation a differential expression and activity of genes and their respective proteins is predicted that modulate signalling properties of the neuronal network including neurotransmission and synaptogenesis (Francks 2011; Margeta and Shen 2010). Indeed, in vertebrate animal models like fish and birds, a clear developmental lateralization programme for body structures has been shown; however, in humans the situation seems to be more complex with independent visceral and brain lateralisation (Tanaka et al. 1999).
Yet, there are only a small number of studies that investigated differential gene expression of brain regions with respect to lateralised gene expression and most of them are hampered by a small sample size of fetal and adult tissues available for analyses related to developmental programmes (Francks 2015). Most of these studies did not reveal any significant difference between left- and right-hemispheric gene expression based on the limited statistical power, however, stringent and region-specific re-analysis of one larger study revealed the first evidence for lateralisation of the expression of a specific set of genes related to synaptic transmission and nervous system development (Karlebach and Francks 2015). How genes identified in the pathogenesis of PD relate to these pathways still needs to be determined, however, mutations in the Parkin gene apparently can be related to strongly lateralised extrapyramidal syndromes (Pramstaller et al. 2002).
Over the last 20 years an increasing number of monogenic forms of PD have been described based on mutations in genes responsible for rare familial forms of the disease (Lill 2016). Most of them account for typical forms of PD that are clinically indistinguishable from the sporadic idiopathic form of the disease and indeed variants in the same genes causing familial PD have been subsequently identified as risk factors for sporadic PD cases (Nalls et al. 2014; Schiesling et al. 2008). The monogenic forms of PD thus present with a similar unilateral onset and develop bilaterally with maintained asymmetry over the course of the disease (Krüger et al. 2001; Lohmann et al. 2003a, b; Zimprich et al. 2004). This asymmetry was further confirmed by functional brain imaging studies in affected mutation carriers using PET and SPECT analyses that showed reduced tracer uptake in the striatum contralateral to the clinically most affected side (Adams et al. 2005; Krüger et al. 2001). This was even observed in asymptomatic LRRK2 mutation carriers, where it was shown that a higher decline of tracer uptake with a marked asymmetry was observed compared to controls at this presymptomatic stage of PD (Nandhagopal et al. 2008). A recent study of 18 asymptomatic LRRK2 mutation carriers showed functional connectivity reductions between the caudal motor part of the left striatum and the ipsilateral superior parietal lobe and increased connectivity between the right SN and bilateral occipital cortical regions, supporting the concept that altered brain connectivity precedes the onset of motor features in a genetic form of PD (Vilas et al. 2016).
Also, for Parkin mutation carriers, which develop an autosomal-recessively inherited juvenile form of PD, a clinical asymmetry correlated with an asymmetric tracer uptake in functional imaging (Hilker et al. 2001). Intriguingly, also heterozygous carriers of Parkin mutations, which are currently discussed to be at risk to develop the typical late onset form of PD, already displayed a presynaptic DAergic dysfunction as illustrated by functional brain imaging (Hilker et al. 2001).
As already mentioned before, Parkin mutation carriers can present with a specific, highly lateralised and therefore unilateral form of parkinsonism that has been described as hemiparkinsonism-hemiatrophy syndrome. This patient, a compound heterozygous carrier of Parkin mutations, presented not only with unilateral parkinsonism but also with an ipsilateral hemiatrophy of the body (Pramstaller et al. 2002). Interestingly, the asymmetry in clinical presentation was not corresponding to the functional brain imaging via PET, as tracer binding was reduced symmetrically. This dissociation between clinical asymmetry and metabolic markers from brain imaging was different to other cases with hemiparkinsonism-hemiatrophy syndrome but consistently observed in other forms of parkinsonism, e.g., dopa-responsive dystonia. Typically the hemiatrophy in these syndromes is thought to be caused by the typical early presentation of unilateral parkinsonism (mean age at onset 43.7 years with the youngest case described at the age of 15 years) leading to reduced motor activity and resulting atrophy (Dziadkiewicz et al. 2013). However, in this case the hemiatrophy observed was independent from the dopaminergic deficit related to the parkinsonian syndrome and may represent an additional factor leading to the asymmetric clinical presentation of parkinsonism in that patient. As the hemiparkinsonism-hemiatrophy syndrome is rare and many of the cases have been described before the era of genetic diagnostics in PD, the contribution of Parkin mutations beyond the single case described remains unclear. However the early disease onset and the typical association of dystonic features closely resemble phenotypes of Parkin-related cases of juvenile PD (Dziadkiewicz et al. 2013).
Beyond mutations in genes responsible for monogenic forms of PD, there is an increasing number of genetic risk factors ranging from rare variants with substantial effects to common variants with small effects that contribute to the complex genetic architecture of PD (Manolio et al. 2009; Larsen et al. 2018). These forms typically present as sporadic PD and therefore, based on the clinical presentation, no specific features in terms of lateralisation can be expected.
Are there clinical consequences of asymmetry in PD?
It is a fact, that onset of PD in most cases shows asymmetrical pathology of the nigrostriatal DA system. Therefore, it has been assumed that right/left unilateral onset causes variation in loop(s) (dys)function(s) (Leh et al. 2010). If so, it is not farfetched to assume clinical and drug-induced consequences and differences caused by right- or left-onset.
Hypothetically, unilateral onset of PD may contribute to (1) variations of symptom onset, severity of disease, progression rate and prognosis. (2) The compensatory capacity of both hemispheres may well be different and this might influence disease pathology and progression. (3) Provokes right-sided early onset degeneration earlier and more severe onset of depression, anxiety and less creativity? And is there a better prognosis - milder progression - in this type of early right-sided PD pathology? (4) Is early left-sided degenerative onset accompanied by early cognitive problems/dysfunctions, leading to earlier dementive symptomology and poorer prognosis? (5) Are there consequences to be considered with regard to clinical studies evaluating drug efficacy, side effect/adverse reaction profiling? Do we lose information for disease modifying/neuroprotective results if right-onset and left-onset PD patients are tested together and clinical endpoints are not differentiated in these groups? (6) Could non-pharmacological interventions in a unilateral setting-enriched therapy improve both progression and pharmacotherapeutic response?
Because of the assumed importance of asymmetrical processes in early PD we emphasise to enrol not only the basic principles of laterality in PD but also its consequences for disease progression, prognosis and therapeutic strategies in clinical studies designed to test these open questions.
Is there a therapy related to asymmetric drug response?
As evidence suggests an asymmetry of the DAT population and a greater number of D1- and D2-DA receptors in the right striatum this might ascribe for a poor prognosis of left-sided onset PD (Riederer and Sian-Hülsmann 2012). Greater motor improvement was seen in right hemibody PD patients after DAergic therapy (Foster et al. 2009). l-DOPA therapy shows the greatest benefit in motor symptoms on the more affected side. Indeed more recent clinical studies in right-handed PD patients using fMRI to investigate asymmetrical effects of levodopa on the hemodynamic correlates of finger movements showed that levodopa led to larger differences in cerebral activity for movements of the more affected left side. These results of Martinu et al. (2014) suggest an impact of reduced DA in the cortico-striatal system and the action of levodopa is not symmetrical (Martinu et al. 2014). This corresponds to the reports about beneficial effects in patients with unilateral deep-brain stimulation (DBS) of the subthalamic nucleus (STN) (Hershey et al. 2008; Riederer and Sian-Hülsmann 2012).
Improvement as recorded with the UPDRS after unilateral DBS in the more affected side was greater in the contralateral side, while spatial delayed response was more impaired.
In most patients levodopa induced dyskinesias are first exhibited in the more affected side (Colosimo et al. 2010).
Dopamine receptor agonists and levodopa promote motor lateralisation in PD (Androulidakis et al. 2007). Even as such little evidence suggests variation of both pharmacotherapeutic strategies and DBS in right/left-onset PD this also might hold true for appearance and severity of side effects and adverse reactions. If such a working hypothesis holds true, the outcome of clinical studies especially for clinical trials designed to prove neuroprotection and disease modification may be at variance in right/left-onset PD patients (Riederer and Sian-Hülsmann 2012). Also unilateral stimulation via non-pharmacological so-called “enriched therapies” may be suitable to avoid (reduce) neurodegenerative processes in early-onset right or left-onset PD (Riederer and Sian-Hülsmann 2012)
It appears that in the early stages of idiopathic PD there is asymmetric neurodegeneration, which perhaps corresponds to the characteristic unilateral manifestation of motor dysfunction. The neuronal cell loss is contralateral to the side of motor symptom onset. Subsequently, as the disease progresses, bilateral motor symptoms are exhibited, probably relating to a more widespread cell destruction in the two hemispheres. However, the appendicular motor asymmetry often persists.
Lateralisation of motor symptoms and neurodegeneration has two important implications. Firstly, the side of symptom onset (left or right side) may have vital implications about the prognosis of the illness and the rate of disease progression. Secondly, asymmetry of motor dysfunction should be carefully considered for the treatment plan. Indeed, deep brain stimulation in the more affected hemisphere has proved to be more beneficial to appendicular motor symptoms.
Also the right/left side dominant motor symptoms may ascribe for the presence of subgroups in PD. Clearly, this leads to new avenues of exploration in the quest of the pathogenesis of PD.
From this review, it is clear and of utmost interest to perform more clinical, neuropathological and experimental studies to clarify the basis of asymmetry in PD.
The work of RK, GH and PK was supported by grants from the Luxembourg National Research Fund (FNR) within the National Centre of Excellence in Research on Parkinson’s disease (NCER-PD), the PEARL programme (FNR; FNR/P13/6682797 to RK) and by the European Union’s Horizon2020 research and innovation program under grant agreement No. 692320 (CENTRE-PD to RK).
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