Functional connectivity of spoken language processing in early-stage Parkinson’s disease : an MEG study

Parkinson's disease (PD) is a neurodegenerative disorder, well-known for its motor symptoms; however, it also adversely affects cognitive functions, including language, a highly important human ability. PD pathology is associated, even in the early stage of the disease, with alterations in the functional connectivity within corticosubcortical circuitry of the basal ganglia as well as within cortical networks. Here, we investigated functional cortical connectivity related to spoken language processing in early-stage PD patients. We employed a patientfriendly passive attention-free paradigm to probe neurophysiological correlates of language processing in PD patients without confounds related to active attention and overt motor responses. MEG data were recorded from a group of newly diagnosed PD patients and age-matched healthy controls who were passively presented with spoken word stimuli (action and abstract verbs, as well as grammatically correct and incorrect inflectional forms) while focussing on watching a silent movie. For each of the examined linguistic aspects, a logistic regression classifier was used to classify participants as either PD patients or healthy controls based on functional connectivity within the temporo-fronto-parietal cortical language networks. Classification was successful for action verbs (accuracy = 0.781, p-value = 0.003) and, with lower accuracy, for abstract verbs (accuracy = 0.688, pvalue = 0.041) and incorrectly inflected forms (accuracy = 0.648, p-value = 0.021), but not for correctly inflected forms (accuracy = 0.523, p-value = 0.384). Our findings point to quantifiable differences in functional connectivity within the cortical systems underpinning language processing in newly diagnosed PD patients compared to healthy controls, which arise early, in the absence of clinical evidence of deficits in cognitive or general language functions. The techniques presented here may aid future work on establishing neurolinguistic markers to objectively and noninvasively identify functional changes in the brain's language networks even before clinical symptoms emerge.Peer reviewe

Altered sensorimotor cortex noradrenergic function in idiopathic REM sleep behaviour disorder - A PET study

Introduction: Noradrenergic denervation is thought to aggravate motor dysfunction in Parkinson's disease (PD). In a previous PET study with the norepinephrine transporter (NART) ligand C-11-MeNER, we detected reduced NART binding in primary sensorimotor cortex (M1S1) of PD patients. Idiopathic rapid-eye-movement sleep behaviour disorder (iRBD) is a phenotype of prodromal PD. Using C-11-MeNER PET, we investigated whether iRBD patients showed similar NART binding reductions in M1S1 cortex as PD patients. Additionally, we investigated whether C-11-MeNER binding and loss of nigrostriatal dopamine storage capacity measured with F-18-DOPA PET were correlated. Methods: 17 iRBD patients, 16 PD patients with (PDRBD+) and 14 without RBD (PDRBD-), and 25 control subjects underwent C-11-MeNER PET. iRBD patients also had F-18-DOPA PET. Volume-of-interest analyses and voxel-level statistical parametric mapping were performed. Results: Partial-volume corrected C-11-MeNER binding potential (BPND) values in M1S1 differed across the groups (P = 0.022) with the iRBD and PDRBD+ groups showing significant reductions (controls vs. iRBD P = 0.007; control vs. PDRBD+ P = 0.008). Voxel-wise comparisons confirmed reductions of M1S1 C-11-MeNER binding in PD and iRBD patients. Significant correlation was seen between putaminal F-18-DOPA uptake and thalamic C-11-MeNER binding in iRBD patients (r(2) = 0.343, P = 0.013). Conclusions: This study found altered noradrenergic neurotransmission in the M1S1 cortex of iRBD patients. The observed reduction of M1S1 C-11-MeNER binding in iRBD may represent noradrenergic terminal degeneration or physiological down-regulation of NARTs in this prodromal phenotype of PD. The correlation between thalamic C-11-MeNER binding and putaminal F-18-DOPA binding suggests that these neurotransmitter systems degenerate in parallel in the iRBD phenotype of prodromal PD

Microsleep disturbances are associated with noradrenergic dysfunction in Parkinson’s disease

Study ObjectivesParkinson’s disease (PD) commonly involves degeneration of sleep-wake regulating brainstem nuclei; likewise, sleep-wake disturbances are highly prevalent in PD patients. As polysomnography macroparameters typically show only minor changes in PD, we investigated sleep microstructure, particularly cyclic alternating pattern (CAP), and its relation to alterations of the noradrenergic system in these patients.MethodsWe analyzed 27 PD patients and 13 healthy control (HC) subjects who underwent overnight polysomnography and 11C-MeNER positron emission tomography for evaluation of noradrenaline transporter density. Sleep macroparameters, as well as CAP metrics, were evaluated according to the consensus statement from 2001. Statistical analysis comprised group comparisons and correlation analysis of CAP metrics with clinical characteristics of PD patients as well as noradrenaline transporter density.ResultsPD patients and HC subjects were comparable in demographic characteristics (age, sex, body mass index) and polysomnography macroparameters. CAP rate as well as A index differed significantly between groups, with PD patients having a lower CAP rate (46.7 ± 6.6% versus 38.0 ± 11.6%, p = 0.015) and lower A index (49.0 ± 8.7/hour versus 40.1 ± 15.4/hour, p = 0.042). In PD patients, both CAP metrics correlated significantly with diminished noradrenaline transporter density in arousal prompting brainstem nuclei (locus coeruleus, raphe nuclei) as well as arousal propagating brain structures like thalamus and bitemporal cortex.ConclusionsSleep microstructure is more severely altered than sleep macrostructure in PD patients and is associated with widespread dysfunction of the noradrenergic arousal system

Preserved noradrenergic function in Parkinson's disease patients with rest tremor

Noradrenergic neurotransmission may play an important role in tremor modulation through its innervation of key structures of the central tremor circuits. Here, Parkinson's disease (PD) patients with (PDT+) or without (PDT-) rest tremor had C-11-methylreboxetine(C-11-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline terminal function was relatively preserved in PDT+ compared to PDT-. Methods: Sixty-five PD patients and 28 healthy controls (HC) were scanned with C-11-MeNER PET. Patients were categorized as PDT+ if subscores in UPDRS-III item 3 or MDS-UPDRS-III item 17 was >= 2; remaining were categorized as PDT-. Simplified reference tissue model 2 distribution volume ratios (DVR) for C-11-MeNER were calculated for thalamus, dorsal and median raphe, locus coeruleus (LC) and red nucleus using time activity curves (TACs) obtained from volumes of interest (VOI). Data were statistically interrogated with a general linear mixed model using 'region', and 'group' as factors and the interaction of 'region x group' was examined. Results: Tremor positive PD patients had a significantly higher mean C-11-MeNER DVR compared to PDT- in LC and thalamus. The PDT+ mean LC DVR was similar to that of HC. PDT+ mean C-11-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PDT- group showed significantly lower mean C-11-MeNER DVR across all regions compared to HC. Conclusion: While both PD (T+) and PD (T-) groups showed a significant loss of noradrenaline terminal function compared to controls, noradrenergic neurons were relatively preserved in PDT+ in LC and thalamus. The greater loss of noradrenergic transporters in PDT- in LC and thalamus compared with PDT+ is in line with earlier in-vitro studies and could potentially contribute to their tremor negative phenotype

Regional locus coeruleus degeneration is uncoupled from noradrenergic terminal loss in Parkinson’s disease

Previous studies have reported substantial involvement of the noradrenergic system in Parkinson’s disease. Neuromelanin-sensitive MRI sequences and PET tracers have become available to visualize the cell bodies in the locus coeruleus and the density of noradrenergic terminal transporters.Combining these methods, we investigated the relationship of neurodegeneration in these distinct compartments in Parkinson’s disease. We examined 93 subjects (40 healthy controls and 53 Parkinson’s disease patients) with neuromelanin-sensitive turbo spin-echo MRI and calculated locus coeruleus-to-pons signal contrasts. Voxels with the highest intensities were extracted from published locus coeruleus coordinates transformed to individual MRI. To also investigate a potential spatial pattern of locus coeruleus degeneration, we extracted the highest signal intensities from the rostral, middle, and caudal third of the locus coeruleus. Additionally, a study-specific probabilistic map of the locus coeruleus was created and used to extract mean MRI contrast from the entire locus coeruleus and each rostro-caudal subdivision. Locus coeruleus volumes were measured using manual segmentations