Healthcare workers' SARS-CoV-2 infection rates during the second wave of the pandemic: follow-up study.

OBJECTIVES: This study aimed to assess if, during the second wave of the COVID-19 pandemic, healthcare workers had increased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates, following close contact with patients, co-workers and persons outside work with COVID-19. METHODS: A follow-up study of 5985 healthcare workers from Denmark was conducted between November 2020 and April 2021 and provided day-to-day information on COVID-19 contacts. SARS-CoV-2 infection was defined by the first positive polymerase chain reaction (PCR) test ever. Data was analyzed in multivariable Poisson regression models. RESULTS: The SARS-CoV-2 infection rates following close contact 3-7 days earlier with patients, co-workers and persons outside work with COVID-19 were 153.7, 240.8, and 728.1 per 100 000 person-days, respectively. This corresponded with age, sex, month, number of PCR tests and mutually adjusted incidence rate ratios of 3.17 [40 cases, 95% confidence interval (CI) 2.15-4.66], 2.54 (10 cases, 95% CI 1.30-4.96) and 17.79 (35 cases, 95% CI 12.05-26.28). The risk of SARS-CoV-2 infection was thus lower, but the absolute numbers affected was higher following COVID-19 contact at work than COVID-19 contact off work. CONCLUSIONS: Despite strong focus on preventive measures during the second wave of the pandemic, healthcare workers were still at increased risk of SARS-CoV-2 infection when in close contact with patients or co-workers with COVID-19. There is a need for increased focus on infection control measures in order to secure healthcare workers' health and reduce transmission into the community during ongoing and future waves of SARS-CoV-2 and other infections.

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 cortico-subcortical 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 patient-friendly 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, p-value = 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.

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. A subset of 73 subjects had 11C-MeNER PET to determine noradrenaline transporter density, and distribution volume ratios of noradrenaline transporter-rich regions were computed. Patients with Parkinson's disease showed reduced locus coeruleus MRI contrast independently of the selected method (voxel approaches: P < 0.0001, P < 0.001; probabilistic map: P < 0.05), specifically on the clinically-defined most affected side (P < 0.05), and reduced locus coeruleus volume (P < 0.0001). Reduced MRI contrast was confined to the middle and caudal locus coeruleus (voxel approach, rostral: P = 0.48, middle: P < 0.0001, and caudal: P < 0.05; probabilistic map, rostral: P = 0.90, middle: P < 0.01, and caudal: P < 0.05). The noradrenaline transporter density was lower in patients with Parkinson's diseasein all examined regions (group effect P < 0.0001). No significant correlation was observed between locus coeruleus MRI contrast and noradrenaline transporter density. In contrast, the individual ratios of noradrenaline transporter density and locus coeruleus MRI contrast were lower in Parkinson's disease patients in all examined regions (group effect P < 0.001). Our multimodal imaging approach revealed pronounced noradrenergic terminal loss relative to cellular locus coeruleus degeneration in Parkinson's disease; the latter followed a distinct spatial pattern with the middle-caudal portion being more affected than the rostral part. The data shed first light on the interaction between the axonal and cell body compartments and their differential susceptibility to neurodegeneration in Parkinson's disease, which may eventually direct research towards potential novel treatment approaches.

Microsleep disturbances are associated with noradrenergic dysfunction in Parkinson's disease.

STUDY OBJECTIVES: Parkinson'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. METHODS: We 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. RESULTS: PD 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. CONCLUSIONS: Sleep 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 11C-methylreboxetine(11C-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 11C-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 11C-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 11C-MeNER DVR compared to PDT- in LC and thalamus. The PDT+ mean LC DVR was similar to that of HC. PDT+ mean 11C-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PDT- group showed significantly lower mean 11C-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.

Molecular Imaging of the Noradrenergic System in Idiopathic Parkinson's Disease.

Noradrenergic neurons in both the peripheral nervous system and in the central nervous system (CNS) undergo severe degeneration in patients with Parkinson's disease (PD). This loss of noradrenaline may play essential roles in the occurrence of a wide range of prevalent non-motor symptoms and can further complicate the lives of PD patients. In vivo molecular imaging of noradrenaline may provide insights into to the extent of degeneration of noradrenergic neurons and subsequent depletion of noradrenergic projections. Molecular imaging methods exist to quantify the noradrenergic deficiency in peripheral autonomic terminals, such as [123I]-meta-iodobenzylguanidin scintigraphy of the heart. However, the degeneration of noradrenergic nuclei in the brainstem and their projections to the CNS has only been quantified with non-selective positron emission tomography ligands in previous studies. Here, we review recent advances in in vivo molecular imaging techniques that evaluate the role of deficits of noradrenaline in PD patients in the manifestation of motor and non-motor symptoms.

Noradrenergic Deficits in Parkinson Disease Imaged with 11C-MeNER.

Degeneration of noradrenergic neurons may underlie the disabling nonmotor symptoms in patients with Parkinson disease (PD). Quantification of the loss of noradrenergic neurons by means of neuroimaging has been limited by the lack of radioligands that are selective for noradrenergic neurotransmission. The radioligand (S,S)-11C-2-(α-(2-methoxyphenoxy)benzyl)morpholine (11C-MeNER) is a highly selective inhibitor of noradrenaline transporters, and PET studies suggest that this radioligand is suitable for quantitative neuroimaging of noradrenergic deficits in human brain in vivo. In the present investigation, we used PET with 11C-MeNER to map the density of noradrenaline transporters in groups of patients with PD and age-matched healthy controls. Methods: After administration of 11C-MeNER, 15 nondemented patients with PD and 10 healthy subjects underwent 90-min dynamic PET. We determined 11C-MeNER binding potential relative to nondisplaceable binding potential (BPND) by multilinear analysis, simplified reference tissue model 2, and multilinear reference tissue model 2. Results: Metabolism of 11C-MeNER did not differ between groups. The simplified reference tissue model 2 and the multilinear reference tissue model 2 were used to determine 11C-MeNER BPND11C-MeNER BPND was reduced in the PD group compared with the control subjects, with regionally significant declines in the thalamus and nucleus ruber. Tremor was associated with higher tracer binding in the PD group on multivariate regression analysis. Conclusion: To our knowledge, this was the first specific quantification of noradrenergic denervation in PD patients in vivo. In agreement with predictions from determinations in vitro, we discovered a decline of noradrenergic projections in vivo in brain of PD patients.