Introduction
Dementia develops in up to 60% of patients suffering from Parkinson’s disease (PD) (Buter et al.
2008), and importantly contributes to the impairment of the quality of life and to caregiver distress. The mechanisms of PD related dementia (PDD) are still poorly understood. Although the loss of nigrostriatal and corticopetal dopaminergic (and serotonergic and noradrenergic) projection systems may contribute to the development of dementia in PD, it is generally believed that additional mechanisms must be involved, most notably degeneration of cholinergic cortical projections and/or local cortical Lewy body- and tau-pathology.
Most normal cognitive processes require dynamic coordination of activity within and between specialized brain areas (Varela et al.
2001). The way the brain accomplishes such functional coupling has received growing attention in recent years. Synchronization of oscillatory neuronal activity within as well as between brain regions is thought to be a possible mechanism, which can be studied by measuring statistical interdependencies between oscillating neurophysiological signals (Pereda et al.
2005). Using this approach, non invasive neurophysiological studies have demonstrated that synchronization of neuronal activity is associated with a variety of cognitive processes, for example, working memory and processing of stimuli (For reviews see (Uhlhaas and Singer
2006; Schnitzler and Gross
2005; Fries
2005; Stam et al.
2005)).
Patterns of functional connectivity can also be studied in the resting state and may be relevant to our understanding of neurodegenerative disorders (Buckner and Vincent
2007). Changes in resting state functional connectivity have been demonstrated using EEG and MEG in several brain disorders, including multiple sclerosis (Cover et al.
2006), brain duct tumors (Bartolomei et al.
2006), Mild Cognitive Impairment (MCI) (Babiloni et al.
2006; Pijnenburg et al.
2004; Stam et al.
2003) and Alzheimer’s disease (AD) (Stam et al.
2002,
2006; Koenig et al.
2005; Pijnenburg et al.
2004; Babiloni et al.
2004; Berendse et al.
2000; Locatelli et al.
1998; Besthorn et al.
1994; Leuchter et al.
1992).
Changes in functional connectivity have also been reported in non-demented PD patients at several different stages of disease. Using MEG and a general measure of synchronization, the synchronization likelihood (SL) (Stam and van Dijk
2002), in early stage, untreated PD patients, we recently demonstrated increased synchronization for both local and long distance connections in the alpha1 frequency range compared to healthy controls (Stoffers et al.
2008). In advanced, but non-demented PD patients, higher levels of cortico-cortical synchronization in the 10–35 Hz frequency range were correlated with more severe parkinsonism and could be attenuated by treatment with levodopa or deep brain stimulation of the subthalamic nucleus, in parallel with clinical motor improvement, suggesting an association between increased synchronization and impaired motor function (Silberstein et al.
2005). Several other studies also suggest that increased (mainly beta) synchronization in basal ganglia-thalamo-cortical circuits may play an essential pathophysiological role in the development of motor symptoms in PD (For review see (Hammond et al.
2007)).
To date, studies of functional coupling in patients with PD related dementia are not available, and it is therefore fully unknown whether dementia in PD is also characterized by changes in synchronization and if so, whether these changes consist of a progression of changes already present in early stage PD (without dementia) or whether the pattern is more like the changes described in AD.
Recently, using power spectral analysis of MEG data, we found a qualitatively different pattern of slowing of background activity in demented compared to non-demented patients (Bosboom et al.
2006). Whereas in PD without dementia an increase in theta and a decrease of beta power were found compared to healthy controls, in PDD an additional increase of delta relative power and a decrease of alpha band power could be demonstrated relative to the non-demented patients. This raises the question whether changes in resting state functional connectivity in demented PD patients, if present, likewise exhibit a qualitatively different pattern from that observed in non-demented patients, suggesting the involvement of different or at least additional pathophysiological mechanisms.
The aim of this study was to analyze resting state cortico-cortical functional connectivity in non-demented and demented PD patients using the SL as a general measure of synchronization.
Our research questions were:
1.
Is PD related dementia characterized by changes in resting state functional connectivity compared to PD without dementia?
2.
Do the changes in functional connectivity in PDD, if present, reflect a progression of the changes observed in non-demented PD patients or is the pattern similar to the changes recently reported for AD?
Discussion
To our knowledge, this is the first MEG study comparing resting state functional connectivity between demented and non-demented PD patients. Our main findings are a reduction in long distance intrahemispheric, predominantly bilateral fronto-temporal synchronization in the alpha1 and alpha2 bands in demented patients together with a reduction in intertemporal synchronization in the 0.5–10 Hz frequency range. In addition, local and interhemispheric gamma band synchronization in centro-parietal regions is lower in demented PD patients, whereas left sided parieto-occipital synchronization in the alpha2 and beta band is higher in the demented patients.
Changes in functional connectivity have been reported in non-demented PD patients in several stages of disease. In very early stage, untreated, non-demented patients, we recently found increased alpha1 synchronization (Stoffers et al.
2008). In moderately advanced patients, the increase in functional connectivity involved a more extended frequency range, also including the theta, alpha2 and beta bands (Stoffers et al.
2008). In advanced stage non-demented PD patients receiving deep brain stimulation, Silberstein et al. found a correlation between higher cortico-cortical coupling in the beta band and more impaired motor function (Silberstein et al.
2005).
In the present study, we report a completely different pattern of changes in demented PD patients in comparison to non-demented patients, mainly consisting of reductions in long-distance fronto-temporal and intertemporal functional connectivity as well as in short distance functional connectivity in several frequency bands.
Combining the results of the present and previous studies, there appear to be differential patterns of change in functional connectivity when comparing between groups of PD patients in different stages of disease and between PD patients and controls. It is therefore tempting to speculate that there are stage-specific patterns of change in synchronization in PD. According to the neuropathological staging system for PD (Braak et al.
2003), the earlier stages of PD are mainly characterized by degeneration of dopaminergic (and serotonergic and noradrenergic) ascending pathways. This would suggest that changes in these neurotransmitter systems might be involved in the increases of functional connectivity observed in early stage non-demented patients. Indeed, the results of the study by Silberstein seem to point to a modulatory role of dopaminomimetic treatment on cortico-cortical synchronization (Silberstein et al.
2005). The qualitatively completely different pattern of changes in dementia in PD we report in this study, however, suggests that these changes are not just related to progression of the above mentioned degeneration of neurotransmitter systems already involved in non-demented PD, but that additional mechanisms are involved.
In AD, using coherence and more recently, the SL, reductions of general synchronization as well as loss of functional connectivity in the alpha and gamma bands have been demonstrated in patients compared to healthy controls in EEG as well as MEG studies (Koenig et al.
2005; Pijnenburg et al.
2004; Stam et al.
2003,
2002,
2006; Berendse et al.
2000; Besthorn et al.
1994). In several studies, the decrease of synchronous activity was correlated with worse cognition (lower MMSE scores) (Stam et al.
2006,
2003; Locatelli et al.
1998). Interestingly, this pattern of changes reported in AD is very similar to the loss of long-distance fronto-temporal and intertemporal resting state functional connectivity we demonstrate in the present study in demented PD patients. Recently, in dementia with Lewy bodies (DLB), a disease considered to be part of the same disease spectrum as PDD, a reduction of long distance intrahemispheric functional coupling in the alpha frequency range, as measured with coherence, has been reported in an MEG study (Franciotti et al.
2006).
Given the similarities in the pattern of reduction of synchronization in AD, DLB and PDD, common pathophysiological mechanisms may be underlying changes in these conditions. A possible common candidate accounting for the loss of synchronization could be the profound loss of cortical cholinergic projections from the basal nucleus of Meynert, since this is a characteristic of AD, DLB and PDD (Braak et al.
2003; Londos et al.
2002; Lippa et al.
1999; Cullen and Halliday
1998; Lehericy et al.
1993; Vogels et al.
1990; Candy et al.
1983). Involvement of the cholinergic system is supported by an animal study, in which lesioning of the cholinergic system resulted in a reduction of long distance intrahemispheric as well as interhemispheric coherence (Holschneider et al.
1999). Furthermore, even in young and elderly healthy subjects, a reduction in interhemispheric EEG and MEG coherence can be demonstrated after the administration of the anticholinergic drug scopolamine (Osipova et al.
2003; Kikuchi et al.
2000), which has been shown to be able to cause temporary cognitive deficits in healthy subjects (Broks et al.
1988; Sunderland et al.
1986).
In addition to a decrease of long distance intrahemispheric and interhemispheric SL, we found a loss of short range gamma synchronization in centro-parietal regions in PDD. Interestingly, in AD, loss of gamma band synchronization has also been demonstrated using MEG (Stam et al.
2002). Since cholinergic activity is often associated with a shift of the power spectrum to faster frequencies as well as with induction of coherence in the high frequency range (Varela et al.
2001), it could well be that the decrease of gamma synchronization in central and parietal areas also reflects loss of cholinergic activity.
Given the suspected pathophysiological significance of degeneration of the cholinergic system in PD related dementia, it would be extremely interesting to see whether cholinesterase inhibitors are able to (partly) reverse the changes in functional connectivity.
In addition to the cholinergic deficit, especially in relation to the decrease of long distance synchronization, other pathophysiological mechanisms may be involved. It seems obvious that loss of anatomical connections between brain areas may lead to a reduction of functional coupling. In AD, atrophy of the corpus callosum has been shown to be associated with loss of lower interhemispheric coherence (Pogarell et al.
2005). Furthermore, in multiple sclerosis, associated with widespread degeneration of the white matter, and therefore, loss of anatomical connections, a strong reduction in interhemispheric connectivity has been reported (Cover et al.
2006). Especially in demented PD patients cortical atrophy can be found, including atrophy of the temporal lobes (Tam et al.
2005; Junque et al.
2005; Camicioli et al.
2003; Burton et al.
2002). Therefore, cortical atrophy as well as pathological changes in the surviving cortex, such as Lewy body- and/or tau-pathology, may be associated with the loss of functional coupling we report in the present study.
The last observation in the present study is an increase in left posterior synchronization in demented patients in the alpha2 and beta frequency range. Interestingly, a similar posterior increase of synchronization levels has recently also been demonstrated in mildly affected AD patients (Stam et al.
2006). The similarity in these observations might suggest that these changes in functional connectivity might be associated with cognitive impairment. An alternative, but speculative explanation might be that increased synchronization constitutes a compensatory mechanism in relatively healthy networks for the loss of functional connectivity in other more damaged networks.
In the present study, we found hardly any correlation between cognition, as measured with the MMSE, and SL parameters. Several factors might explain the absence of significant correlations. First, the MMSE is a global screening tool for cognitive dysfunction. Impairments in specific cognitive domains that might possibly be related to changes in synchronization are not specifically assessed with this measure. Second, the variance of MMSE scores in our demented PD group was relatively small. Last, our study sample was relatively small, and therefore, correlations might not have reached significance because of a lack of power.
In the future, studies using more specific measures of different cognitive domains, for instance, executive dysfunction, in a larger group of PD patients are needed to further address the relationship between cognitive dysfunction and changes in functional connectivity.
Some possible limitations of our study have to be considered. First, demented patients had significantly higher UPDRS motor scores compared to the non-demented patients. Therefore, it might be argued that our results are partly related to differences in motor function between patient groups. However, for the UPDRS OFF scores, there were no significant results nor even a trend towards significance for any of the SL parameters in the ANOVA with repeated-measures in both the demented and non-demented PD group. Furthermore, previous studies have shown that impaired motor function in early as well as more advanced stage, non-demented PD patients is associated with increases in synchronization (Silberstein et al.
2005; Stoffers et al.
2008)). Since, in the present study, we mainly report significant reductions in the demented patients, it seems highly unlikely that our results can be explained by worse motor function in our demented patients. To the contrary, worse motor function in the demented PD patients might have even partly masked reductions in SL.
Second, MEG correlations between signals from nearby sensors could be due to common sources rather than true interactions. This is the well-known problem of volume conduction that may give rise to spurious correlations in sensor space. One possible solution is to estimate correlations between signals from reconstructed sources (source space) rather than the actually recorded signal (signal space) (Hadjipapas et al.
2005; David et al.
2002; Gross et al.
2001). However, no unique way exists to reconstruct the sources, and the source reconstruction algorithm used could influence the interdependencies between the sources (Hadjipapas et al.
2005). Therefore, in the present study, we used a pragmatic approach, restricting the analysis to signal space. Although volume conduction may influence SL values in this way, it seems unlikely that this can explain major group differences in SL between PDD and PD. Furthermore, the majority of our main results involve changes in long distance interactions which are less likely to be affected by volume conduction.