A three dimensional anatomical view of oscillatory resting-state activity and functional connectivity in Parkinson's disease related dementia: An MEG study using atlas-based beamforming.

Parkinson's disease (PD) related dementia (PDD) develops in up to 80% of PD patients. The present study was performed to further unravel the underlying pathophysiological mechanisms by applying a new analysis approach that uses an atlas-based MEG beamformer to provide a detailed anatomical mapping of cortical rhythms and functional interactions. Importantly, we used the phase lag index (PLI) as a measure of functional connectivity to avoid any biases due to effects of volume conduction. MEG recordings were obtained in 13 PDD and 13 non-demented PD patients. Beamforming was used to estimate spectral power and PLI in delta, theta, alpha, beta and gamma frequency bands. Compared to PD patients, PDD patients had more delta and theta power in parieto-occipital and fronto-parietal areas, respectively. The PDD patients had less alpha and beta power in parieto-temporo-occipital and frontal areas, respectively. Compared to PD patients, PDD patients had lower mean PLI values in the delta and alpha bands in fronto-temporal and parieto-temporo-occipital areas, respectively. In addition, in PDD patients connectivity between pairs of regions of interest (Brodmann areas) was stronger in the theta band and weaker in the delta, alpha and beta bands. The added value of the present results over previous studies analysing frequency-specific changes in neuronal activity in PD patients, is the anatomical framework in which we demonstrated a slowing in neuronal activity and a reduction in functional connectivity in PD related dementia. Moreover, this study shows a widespread reduction in functional connectivity between different regions in PDD.

Cholinergic modulation of MEG resting-state oscillatory activity in Parkinson's disease related dementia.

OBJECTIVE: EEG and MEG studies in Parkinson's disease (PD) related dementia (PDD) have shown a slowing of resting-state, oscillatory activity compared to non demented PD. Aim of the present MEG study was to determine whether treatment with the cholinesterase inhibitor rivastigmine would reverse this slowing of resting-state activity in PDD patients. METHODS: In eight PDD patients, whole head MEG was recorded in a resting-state condition before and after treatment with rivastigmine. Relative spectral power was calculated in the delta, theta, alpha, beta and gamma frequency bands in fronto-central, parieto-occipital and temporal regions. RESULTS: After treatment with rivastigmine, PDD patients demonstrated an increase in relative power in the alpha range in parieto-occipital and temporal regions together with a diffuse increase in beta power. Furthermore, a decrease of delta power in fronto-central and parieto-occipital regions was found. CONCLUSIONS: Treatment with the cholinesterase inhibitor rivastigmine at least partly counteracts the slowing of resting-state brain activity that is known to occur in PD related dementia. SIGNIFICANCE: Our observations emphasize the prominent role of degeneration of the cholinergic system in the pathophysiology of dementia in PD. In the future, MEG might contribute to the selection of PD patients who may optimally benefit from cholinergic treatment.

MEG resting state functional connectivity in Parkinson's disease related dementia.

Parkinson's disease (PD) related dementia (PDD) develops in up to 60% of patients, but the pathophysiology is far from being elucidated. Abnormalities of resting state functional connectivity have been reported in Alzheimer's disease (AD). The present study was performed to determine whether PDD is likewise characterized by changes in resting state functional connectivity. MEG recordings were obtained in 13 demented and 13 non-demented PD patients. The synchronization likelihood (SL) was calculated within and between cortical areas in six frequency bands. Compared to non-demented PD, PDD was characterized by lower fronto-temporal SL in the alpha range, lower intertemporal SL in delta, theta and alpha1 bands as well as decreased centro-parietal gamma band synchronization. In addition, higher parieto-occipital synchronization in the alpha2 and beta bands was found in PDD. The observed changes in functional connectivity are reminiscent of changes in AD, and may reflect reduced cholinergic activity and/or loss of cortico-cortical anatomical connections in PDD.

Increased cortico-cortical functional connectivity in early-stage Parkinson's disease: an MEG study.

We set out to determine whether changes in resting-state cortico-cortical functional connectivity are a feature of early-stage Parkinson's disease (PD), explore how functional coupling might evolve over the course of the disease and establish its relationship with clinical deficits. Whole-head magnetoencephalography was performed in an eyes-closed resting-state condition in 70 PD patients with varying disease duration (including 18 recently diagnosed, drug-naive patients) in an "OFF" medication state and 21 controls. Neuropsychological testing was performed in all subjects. Data analysis involved calculation of three synchronization likelihood (SL, a general measure of linear and non-linear temporal correlations between time series) measures which reflect functional connectivity within (local) and between (intrahemispheric and interhemispheric) ten major cortical regions in five frequency bands. Recently diagnosed, drug-naive patients showed an overall increase in alpha1 SL relative to controls. Cross-sectional analysis in all patients revealed that disease duration was positively associated with alpha2 and beta SL measures, while severity of parkinsonism was positively associated with theta and beta SL measures. Moderately advanced patients had increases in theta, alpha1, alpha2 and beta SL, particularly with regard to local SL. In recently diagnosed patients, cognitive perseveration was associated with increased interhemispheric alpha1 SL. Increased resting-state cortico-cortical functional connectivity in the 8-10 Hz alpha range is a feature of PD from the earliest clinical stages onward. With disease progression, neighboring frequency bands become increasingly involved. These findings suggest that changes in functional coupling over the course of PD may be linked to the topographical progression of pathology over the brain.

Slowing of oscillatory brain activity is a stable characteristic of Parkinson's disease without dementia.

Extensive changes in resting-state oscillatory brain activity have recently been demonstrated using magnetoencephalography (MEG) in moderately advanced, non-demented Parkinson's disease patients relative to age-matched controls. The aim of the present study was to determine the onset and evolution of these changes over the disease course and their relationship with clinical parameters. In addition, we evaluated the effects of dopaminomimetics on resting-state oscillatory brain activity in levodopa-treated patients. MEG background oscillatory activity was studied in a group of 70 Parkinson's disease patients with varying disease duration and severity (including 18 de novo patients) as well as in 21 controls that were age-matched to the de novo patients. Whole head 151-channel MEG recordings were obtained in an eyes-closed resting-state condition. Levodopa-treated patients (N = 37) were examined both in a practically defined 'OFF' as well as in the 'ON' state. Relative spectral power was calculated for delta, theta, low alpha, high alpha, beta and gamma frequency bands and averaged for 10 cortical regions of interest (ROIs). Additionally, extensive clinical and neuropsychological testing was performed in all subjects. De novo Parkinson's disease patients showed widespread slowing of background MEG activity relative to controls. Changes included a widespread increase in theta and low alpha power, as well as a loss of beta power over all but the frontal ROIs and a loss of gamma power over all but the right occipital ROI. Neuropsychological assessment revealed abnormal perseveration in de novo patients, which was associated with increased low alpha power in centroparietal ROIs. In the whole group of Parkinson's disease patients, longer disease duration was associated with reduced low alpha power in the right temporal and right occipital ROI, but not with any other spectral power measure. No association was found between spectral power and disease stage, disease severity or dose of dopaminomimetics. In patients on levodopa therapy, a change from the 'OFF' to the 'ON' state was associated with decreases in right frontal theta, left occipital beta and left temporal gamma power and an increase in right parietal gamma power. Widespread slowing of oscillatory brain activity is a characteristic of non-demented Parkinson's disease patients from the earliest clinical stages onwards that is (largely) independent of disease duration, stage and severity and hardly influenced by dopaminomimetic treatment. Some early cognitive deficits in Parkinson's disease appear to be associated with increased low alpha power. We postulate a role for hypofunctional non-dopaminergic ascending neurotransmitter systems in spectral power changes in non-demented Parkinson's disease patients.

Resting state oscillatory brain dynamics in Parkinson's disease: an MEG study.

OBJECTIVE: The pathophysiological mechanisms of cognitive dysfunction and dementia in Parkinson's disease (PD) are still poorly understood. Altered resting state oscillatory brain activity may reflect underlying neuropathological changes. The present study using magneto encephalography (MEG) was set up to study differences in the pattern of resting state oscillatory brain activity in groups of demented and non-demented PD patients and healthy, elderly controls. METHODS: The pattern of MEG background oscillatory activity was studied in 13 demented PD patients, 13 non-demented PD patients and 13 healthy controls. Whole head MEG recordings were obtained in the morning in an eyes closed and an eyes open, resting state condition. Relative spectral power was calculated using Fast Fourier Transformation in delta, theta, alpha, beta and gamma frequency bands. RESULTS: In the non-demented PD patients, relative theta power was diffusely increased and beta power concomitantly decreased relative to controls. gamma Power was decreased in central and parietal channels. In the demented PD patients, a diffuse increase in relative delta and to lesser extent theta power and a decrease in relative alpha, beta and to lesser extent gamma power were found in comparison to the non-demented PD group. In addition, reactivity to eye opening was much reduced in the demented PD group. CONCLUSIONS: Parkinson's disease is characterized by a slowing of resting state brain activity involving theta, beta and gamma frequency bands. Dementia in PD is associated with a further slowing of resting state brain activity, additionally involving delta and alpha bands, as well as a reduction in reactivity to eye-opening. SIGNIFICANCE: The differential patterns of slowing of resting state brain activity in demented and non-demented PD patients suggests that, in conjunction with a progression of the pathological changes already present in non-demented patients, additional mechanisms are involved in the development of dementia in PD.

Cognitive dysfunction and dementia in Parkinson's disease.

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder mainly characterized by degeneration of dopaminergic neurons in the substantia nigra and the ventral tegmental area, in combination with a varying loss of central noradrenergic (locus coeruleus), cholinergic (nucleus basalis of Meynert) and serotonergic (dorsal raphe nuclei) integrity, leading to a multitude of motor and non-motor behavioral disturbances. Apart from the clinical motor hallmarks, in the early stages of disease, subtle cognitive dysfunction might be seen comprising mainly executive dysfunction, with secondary visuospatial and mnemonic disturbances. In about 20-40% of patients, these problems may eventually proceed to dementia, which constitutes an important risk factor for caregiver distress, decreased quality of life and nursing home placement. Dementia in PD is typically characterized by a progressive dysexecutive syndrome with attentional deficits and fluctuating cognition, often accompanied by psychotic symptoms. It is thought to be the result of a combination of both subcortical and cortical changes. PD-related dopaminergic deficiency in the nucleus caudatus and mesocortical areas (due to degeneration of projections from the substantia nigra and ventral tegmental area) and cholinergic deficiency in the cortex (due to degeneration of ascending projections from the nucleus basalis of Meynert), combined with additional Alzheimer-pathology and cortical Lewy bodies, may greatly contribute to dementia. Current treatment of dementia in PD is based on compensation of the profound cholinergic deficiency. Recent studies with the cholinesterase inhibitors galantamine, donepezil and rivastigmine show promising results in improving cognition and ameliorating psychotic symptoms, which must further be confirmed in randomized controlled trials.

Psychotic symptoms in Parkinson's disease: pathophysiology and management.

Parkinson's disease (PD) is a chronic neurodegenerative disease, in which mainly dopaminergic neurons in the substantia nigra in the brain degenerate, leading to a depletion of dopamine (DA) in the striatum. The most important motor disturbances of the disease are bradykinesia (slowing down of movement), hypokinesia (poverty of movement), rigidity (muscle stiffness), tremor and postural instability. Besides these well-known motor symptoms, non-motor symptoms may develop, such as depression, cognitive impairment and psychosis. Psychotic symptoms constitute a relatively common but nevertheless serious complication, with visual hallucinations and paranoid delusions often being most prominent. These symptoms are important contributors to patient and caregiver distress and are often important risk factors for nursing home placement. Exogenous (related to therapeutic interventions) factors are of major importance but endogenous (related to the disease process itself) factors might also contribute to the development of psychotic symptoms in PD. Therapeutic strategies comprise reduction of antiparkinsonian treatment, cholinesterase inhibitors and atypical antipsychotics. As psychotic symptoms in PD are often influenced by both endogenous and exogenous factors, a combination of strategies may be chosen.

The role of acetylcholine and dopamine in dementia and psychosis in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurological disorder in which there is abnormal degeneration of dopaminergic neurons in the substantia nigra and the ventral tegmental area combined with a varying degree of deterioration of the cholinergic, serotonergic and noradrenergic system, leading to a variety of motor and non-motor abnormalities. Dopamine (DA) depletion in nigrostriatal projections manifests with abnormal spontaneous motor behavior and (subtle) cognitive deficits, whereas more overt cognitive impairment may develop with concomitant DA-deficiency related mesocorticolimbic denervation. In combination with a progressive dysfunction of the ascending neocortical cholinergic (and serotonergic and noradrenergic) projections, mainly due to a loss of cholinergic neurons in the nucleus basalis of Meynert (NbM), these cognitive deficits may proceed into dementia sometimes in combination with psychotic behavior, which might also be associated with dopaminomimetic and/or anticholinergic treatment as well as with cholinergic deficit or dopaminomimetic induced REM sleep disturbances. As these psychiatric symptoms have a substantial negative effect on the patient's quality of life, contribute to caregiver distress and are predictive of nursing home placement, identification and adequate treatment is of great importance. Recent evidence supports a possible role for cholinomimetic therapy in alleviating cognitive dysfunction and psychotic symptoms in PD.