Microglial Activation and Progression of Nigrostriatal Dysfunction in Isolated REM Sleep Behavior Disorder.

BACKGROUND: Using 11C-(R)-PK11195-PET, we found increased microglia activation in isolated REM sleep behavior disorder (iRBD) patients. Their role remains to be clarified. OBJECTIVES: The objective is to assess relationships between activated microglia and progression of nigrostriatal dysfunction in iRBD. METHODS: Fifteen iRBD patients previously scanned with 11C-(R)-PK11195 and 18F-DOPA-PET underwent repeat 18F-DOPA-PET after 3 years. 18F-DOPA Ki changes from baseline were evaluated with volumes-of-interest and voxel-based analyses. RESULTS: Significant 18F-DOPA Ki reductions were found in putamen and caudate. Reductions were larger and more widespread in patients with increased nigral microglia activation at baseline. Left nigral 11C-(R)-PK11195 binding at baseline was a predictor of 18F-DOPA Ki reduction in left caudate (coef = -0.0426, P = 0.016). CONCLUSIONS: Subjects with increased baseline 11C-(R)-PK11195 binding have greater changes in nigrostriatal function, suggesting a detrimental rather than protective effect of microglial activation. Alternatively, both phenomena occur in patients with prominent nigrostriatal dysfunction without a causative link. The clinical and therapeutic implications of these findings need further elucidation. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Progression of brain cholinergic dysfunction in patients with isolated rapid eye movement sleep behavior disorder.

BACKGROUND: Reduced cortical acetylcholinesterase activity, as measured by 11 C-donepezil positron emission tomography (PET), has been reported in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD). However, its progression and clinical implications have not been fully investigated. Here, we explored the relationship between longitudinal changes in brain acetylcholinesterase activity and cognitive function in iRBD. METHODS: Twelve iRBD patients underwent 11 C-donepezil PET at baseline and after 3 years. PET images were interrogated with statistical parametric mapping (SPM) and a regions of interest (ROI) approach. Clinical progression was assessed with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). Cognitive function was rated using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). RESULTS: From baseline to follow-up, the mean 11 C-donepezil distribution volume ratio (DVR) decreased in the cortex (p = 0.006), thalamus (p = 0.013), and caudate (p = 0.013) ROI. Despite no significant changes in the group mean MMSE or MoCA scores being observed, individually, seven patients showed a decline in their scores on these cognitive tests. Subgroup analysis showed that only the subgroup of patients with a decline in cognitive scores had a significant reduction in mean cortical 11 C-donepezil DVR. CONCLUSIONS: Our results show that severity of brain cholinergic dysfunction in iRBD patients increases significantly over 3 years, and those changes are more severe in those with a decline in cognitive test scores.

Cholinergic dysfunction in isolated rapid eye movement sleep behaviour disorder links to impending phenoconversion.

BACKGROUND AND PURPOSE: Most patients with isolated rapid eye movement sleep behaviour disorder (iRBD) progress to a parkinsonian alpha-synucleinopathy. However, time to phenoconversion shows great variation. The aim of this study was to investigate whether cholinergic and dopaminergic dysfunction in iRBD patients was associated with impending phenoconversion. METHODS: Twenty-one polysomnography-confirmed iRBD patients underwent baseline 11C-donepezil and 6-Fluoro-(18F)-l-3,4-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET). Potential phenoconversion was monitored for up to 8 years. PET images were analysed according to patients' diagnoses after 3 and 8 years using linear regression. Time-to-event analysis was made with Cox regression, dividing patients into low and high tracer uptake groups. RESULTS: Follow-up was accomplished in 17 patients. Eight patients progressed to either Parkinson's disease (n = 4) or dementia with Lewy bodies (n = 4), while nine remained non-phenoconverters. Compared with non-phenoconverters, 8-year phenoconverters had lower mean 11C-donepezil uptake in the parietal (p = 0.032) and frontal cortex (p = 0.042), whereas mean 11C-donepezil uptake in 3-year phenoconverters was lower in the parietal cortex (p = 0.005), frontal cortex (p = 0.025), thalamus (p = 0.043) and putamen (p = 0.049). Phenoconverters within 3 years and 8 years had lower 18F-DOPA uptake in the putamen (p < 0.001). iRBD patients with low parietal 11C-donepezil uptake had a 13.46 (95% confidence interval 1.42;127.21) times higher rate of phenoconversion compared with those with higher uptake (p = 0.023). iRBD patients with low 18F-DOPA uptake in the most affected putamen were all phenoconverters with higher rate of phenoconversion (p = 0.0002). CONCLUSIONS: These findings suggest that cortical cholinergic dysfunction, particularly within the parietal cortex, could be a biomarker candidate for predicting short-term phenoconversion in iRBD patients. This study aligns with previous reports suggesting dopaminergic dysfunction is associated with forthcoming phenoconversion.

Monocyte markers correlate with immune and neuronal brain changes in REM sleep behavior disorder.

Synucleinopathies are neurodegenerative diseases with both central and peripheral immune responses. However, whether the peripheral immune changes occur early in disease and their relation to brain events is yet unclear. Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) can precede synucleinopathy-related parkinsonism and provides a prodromal phenotype to study early Parkinson's disease events. In this prospective case-control study, we describe monocytic markers in a cohort of iRBD patients that were associated with the brain-imaging markers of inflammation and neuronal dysfunction. Using 11C-PK11195 positron emission tomography (PET), we previously showed increased immune activation in the substantia nigra of iRBD patients, while 18F-DOPA PET detected reduced putaminal dopaminergic function. Here we describe that patients' blood monocytic cells showed increased expression of CD11b, while HLA-DR expression was decreased compared to healthy controls. The iRBD patients had increased classical monocytes and mature natural killer cells. Remarkably, the levels of expression of Toll-like receptor 4 (TLR4) on blood monocytes in iRBD patients were positively correlated with nigral immune activation measured by 11C-PK11195 PET and negatively correlated with putaminal 18F-DOPA uptake; the opposite was seen for the percentage of CD163+ myeloid cells. This suggesting a deleterious role for TLR4 and, conversely, a protective one for the CD163 expression. We show an association between peripheral blood monocytes and brain immune and dopaminergic changes in a synucleinopathy-related disorder, thus suggesting a cross-talk among periphery and brain during the disease.

Impaired cerebral microcirculation in isolated REM sleep behaviour disorder.

During the prodromal period of Parkinson's disease and other α-synucleinopathy-related parkinsonisms, neurodegeneration is thought to progressively affect deep brain nuclei, such as the locus coeruleus, caudal raphe nucleus, substantia nigra, and the forebrain nucleus basalis of Meynert. Besides their involvement in the regulation of mood, sleep, behaviour, and memory functions, these nuclei also innervate parenchymal arterioles and capillaries throughout the cortex, possibly to ensure that oxygen supplies are adjusted according to the needs of neural activity. The aim of this study was to examine whether patients with isolated REM sleep behaviour disorder, a parasomnia considered to be a prodromal phenotype of α-synucleinopathies, reveal microvascular flow disturbances consistent with disrupted central blood flow control. We applied dynamic susceptibility contrast MRI to characterize the microscopic distribution of cerebral blood flow in the cortex of 20 polysomnographic-confirmed patients with isolated REM sleep behaviour disorder (17 males, age range: 54-77 years) and 25 healthy matched controls (25 males, age range: 58-76 years). Patients and controls were cognitively tested by Montreal Cognitive Assessment and Mini Mental State Examination. Results revealed profound hypoperfusion and microvascular flow disturbances throughout the cortex in patients compared to controls. In patients, the microvascular flow disturbances were seen in cortical areas associated with language comprehension, visual processing and recognition and were associated with impaired cognitive performance. We conclude that cortical blood flow abnormalities, possibly related to impaired neurogenic control, are present in patients with isolated REM sleep behaviour disorder and associated with cognitive dysfunction. We hypothesize that pharmacological restoration of perivascular neurotransmitter levels could help maintain cognitive function in patients with this prodromal phenotype of parkinsonism.

Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study.

Parkinson's disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial α-synuclein aggregates originate. We have hypothesized that Parkinson's disease comprises two subtypes. A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type. Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups. We included 37 consecutive de novo patients with Parkinson's disease into this case-control PET study. Patients with Parkinson's disease were divided into 24 RBD-negative (PDRBD-) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients. We used 11C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity. Colon volume and transit times were assessed with CT scans and radiopaque markers. Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons. The PDRBD- and PDRBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P < 10-13, ANOVA). When compared to the PDRBD- patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P < 10-5, ANOVA) and colon 11C-donepezil standard uptake values (P = 0.008, ANOVA). The PDRBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PDRBD- (P = 0.07, t-test). In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (P < 0.001, ANOVA) and delayed colonic transit times (P = 0.01, Kruskal-Wallis). The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake. In contrast, the PDRBD- data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal. These findings support the existence of brain-first and body-first subtypes of Parkinson's disease.

Ear-EEG for sleep assessment: a comparison with actigraphy and PSG.

PURPOSE: To assess automatic sleep staging of three ear-EEG setups with different electrode configurations and compare performance with concurrent polysomnography and wrist-worn actigraphy recordings. METHODS: Automatic sleep staging was performed for single-ear, single-ear with ipsilateral mastoid, and cross-ear electrode configurations, and for actigraphy data. The polysomnography data were manually scored and used as the gold standard. The automatic sleep staging was tested on 80 full-night recordings from 20 healthy subjects. The scoring performance and sleep metrics were determined for all ear-EEG setups and the actigraphy device. RESULTS: The single-ear, the single-ear with ipsilateral mastoid setup, and the cross-ear setup performed five class sleep staging with kappa values 0.36, 0.63, and 0.72, respectively. For the single-ear with mastoid electrode and the cross-ear setup, the performance of the sleep metrics, in terms of mean absolute error, was better than the sleep metrics estimated from the actigraphy device in the current study, and also better than current state-of-the-art actigraphy studies. CONCLUSION: A statistically significant improvement in both accuracy and kappa was observed from single-ear to single-ear with ipsilateral mastoid, and from single-ear with ipsilateral mastoid to cross-ear configurations for both two and five-sleep stage classification. In terms of sleep metrics, the results were more heterogeneous, but in general, actigraphy and single-ear with ipsilateral mastoid configuration were better than the single-ear configuration; and the cross-ear configuration was consistently better than both the actigraphy device and the single-ear configuration.

A randomized controlled trial of bedtime music for insomnia disorder.

Music is often used as a self-help tool to alleviate insomnia. To evaluate the effect of bedtime music listening as a strategy for improving insomnia, we conducted an assessor-blinded randomized controlled trial. Fifty-seven persons with insomnia disorder were included and randomized to music intervention (n = 19), audiobook control (n = 19) or a waitlist control group (n = 19). The primary outcome measure was the Insomnia Severity Index. In addition, we used polysomnography and actigraphy to evaluate objective measures of sleep, and assessed sleep quality and quality of life. The results showed no clear effect of music on insomnia symptoms as the group × time interaction only approached significance (effect size = 0.71, p = .06), though there was a significant improvement in insomnia severity within the music group. With regard to the secondary outcomes, we found a significant effect of the music intervention on perceived sleep improvement and quality of life, but no changes in the objective measures of sleep. In conclusion, music listening at bedtime appears to have a positive impact on sleep perception and quality of life, but no clear effect on insomnia severity. Music is safe and easy to administer, but further research is needed to assess the effect of music on different insomnia subtypes, and as an adjunctive or preventive intervention.

Evaluation of the noradrenergic system in Parkinson's disease: an 11C-MeNER PET and neuromelanin MRI study.

Pathological involvement of the noradrenergic locus coeruleus occurs early in Parkinson's disease, and widespread noradrenaline reductions are found at post-mortem. Rapid eye movement sleep behaviour disorder (RBD) accompanies Parkinson's disease and its presence predicts an unfavourable disease course with a higher propensity to cognitive impairment and orthostatic hypotension. MRI can detect neuromelanin in the locus coeruleus while 11C-MeNER PET is a marker of noradrenaline transporter availability. Here, we use both imaging modalities to study the association of RBD, cognition and autonomic dysfunction in Parkinson's disease with loss of noradrenergic function. Thirty non-demented Parkinson's disease patients [16 patients with RBD and 14 without RBD, comparable across age (66.6 ± 6.7 years), sex (22 males), and disease stage (Hoehn and Yahr, 2.3 ± 0.5)], had imaging of the locus coeruleus with neuromelanin sensitive MRI and brain noradrenaline transporter availability with 11C-MeNER PET. RBD was confirmed with polysomnography; cognitive function was assessed with a neuropsychological test battery, and blood pressure changes on tilting were documented; results were compared to 12 matched control subjects. We found that Parkinson's disease patients with RBD showed decreased locus coeruleus neuromelanin signal on MRI (P < 0.001) and widespread reduced binding of 11C-MeNER (P < 0.001), which correlated with amount of REM sleep without atonia. Parkinson's disease with RBD was also associated with a higher incidence of cognitive impairment, slowed EEG activity, and orthostatic hypotension. Reduced 11C-MeNER binding correlated with EEG slowing, cognitive performance, and orthostatic hypotension. In conclusion, reduced noradrenergic function in Parkinson's disease was linked to the presence of RBD and associated with cognitive deterioration and orthostatic hypotension. Noradrenergic impairment may contribute to the high prevalence of these non-motor symptoms in Parkinson's disease, and may be of relevance when treating these conditions in Parkinson's disease.

Extrastriatal monoaminergic dysfunction and enhanced microglial activation in idiopathic rapid eye movement sleep behaviour disorder.

BACKGROUND: The majority of patients diagnosed with idiopathic rapid eye movement sleep behaviour disorder (iRBD) progress over time to a Lewy-type α-synucleinopathy such as Parkinson's disease or dementia with Lewy bodies. This in vivo molecular imaging study aimed to investigate if extrastriatal monoaminergic systems are affected in iRBD patients and if this coincides with neuroinflammation. METHODS: We studied twenty-one polysomnography-confirmed iRBD patients with 18F-DOPA and 11C-PK11195 positron emission tomography (PET) to investigate extrastriatal monoaminergic function and microglial activation. Twenty-nine healthy controls (n = 9 18F-DOPA and n = 20 11C-PK11195) were also investigated. Analyses were performed within predefined regions of interest and at voxel-level with Statistical Parametric Mapping. RESULTS: Regions of interest analysis detected monoaminergic dysfunction in iRBD thalamus with a 15% mean reduction of 18F-DOPA Ki values compared to controls (mean difference = -0.00026, 95% confidence interval [-0.00050 to -0.00002], p-value = 0.03). No associated thalamic changes in 11C-PK11195 binding were observed. Other regions sampled showed no 18F-DOPA or 11C-PK11195 PET differences between groups. Voxel-level interrogation of 11C-PK11195 binding identified areas with significantly increased binding within the occipital lobe of iRBD patients. CONCLUSION: Thalamic monoaminergic dysfunction in iRBD patients may reflect terminal dysfunction of projecting neurons from the locus coeruleus and dorsal raphe nucleus, two structures that regulate REM sleep and are known to be involved in the early phase of PD. The observation of significantly raised microglial activation in the occipital lobe of these patients might suggest early local Lewy-type α-synuclein pathology and possibly an increased risk for later cognitive dysfunction.

Automatic sleep staging using ear-EEG.

BACKGROUND: Sleep and sleep quality assessment by means of sleep stage analysis is important for both scientific and clinical applications. Unfortunately, the presently preferred method, polysomnography (PSG), requires considerable expert assistance and significantly affects the sleep of the person under observation. A reliable, accurate and mobile alternative to the PSG would make sleep information much more readily available in a wide range of medical circumstances. NEW METHOD: Using an already proven method, ear-EEG, in which electrodes are placed inside the concha and ear canal, we measure cerebral activity and automatically score the sleep into up to five stages. These results are compared to manual scoring by trained clinicians, based on a simultaneously recorded PSG. RESULTS: The correspondence between manually scored sleep, based on the PSG, and the automatic labelling, based on ear-EEG data, was evaluated using Cohen's kappa coefficient. Kappa values are in the range 0.5-0.8, making ear-EEG relevant for both scientific and clinical applications. Furthermore, a sleep-wake classifier with leave-one-out cross validation yielded specificity of 0.94 and sensitivity of 0.52 for the sleep stage. COMPARISON WITH EXISTING METHOD(S): Ear-EEG based scoring has clear advantages when compared to both the PSG and other mobile solutions, such as actigraphs. It is far more mobile, and potentially cheaper than the PSG, and the information on sleep stages is far superior to a wrist-based actigraph, or other devices based solely on body movement. CONCLUSIONS: This study shows that ear-EEG recordings carry information about sleep stages, and indicates that automatic sleep staging based on ear-EEG can classify sleep stages with a level of accuracy that makes it relevant for both scientific and clinical sleep assessment.

Spontaneous electromyographic activity of the tongue in amyotrophic lateral sclerosis.

INTRODUCTION: Detection of denervation in muscles in the craniobulbar area is important to assure widespread lower motor neuron involvement in the diagnosis of amyotrophic lateral sclerosis (ALS). The value of spontaneous activity analysis in needle electromyography (EMG) of the tongue has been questioned in the recent literature. METHODS: Spontaneous activity in the tongue and sternocleidomastoid (SCM) muscles was reviewed retrospectively in 17 ALS patients. RESULTS: Needle EMG showed spontaneous activity in the tongue in 14 of 17 patients (82%) and in 6 patients of 17 (35%) in SCM. Spontaneous EMG activity in the tongue was found in patients with and without bulbar symptoms. CONCLUSIONS: Needle EMG is a valuable method for assessing clinical and subclinical involvement of the tongue in patients with bulbar and limb onset ALS. Adequate relaxation of the tongue is a prerequisite for proper spontaneous activity recording.

At-home sleep monitoring using generic ear-EEG.

Introduction: A device comprising two generic earpieces with embedded dry electrodes for ear-centered electroencephalography (ear-EEG) was developed. The objective was to provide ear-EEG based sleep monitoring to a wide range of the population without tailoring the device to the individual. Methods: To validate the device ten healthy subjects were recruited for a 12-night sleep study. The study was divided into two parts; part A comprised two nights with both ear-EEG and polysomnography (PSG), and part B comprised 10 nights using only ear-EEG. In addition to the electrophysiological measurements, subjects filled out a questionnaire after each night of sleep. Results: The subjects reported that the ear-EEG system was easy to use, and that the comfort was better in part B. The performance of the system was validated by comparing automatic sleep scoring based on ear-EEG with PSG-based sleep scoring performed by a professional trained sleep scorer. Cohen's kappa was used to assess the agreement between the manual and automatic sleep scorings, and the study showed an average kappa value of 0.71. The majority of the 20 recordings from part A yielded a kappa value above 0.7. The study was compared to a companioned study conducted with individualized earpieces. To compare the sleep across the two studies and two parts, 7 different sleeps metrics were calculated based on the automatic sleep scorings. The ear-EEG nights were validated through linear mixed model analysis in which the effects of equipment (individualized vs. generic earpieces), part (PSG and ear-EEG vs. only ear-EEG) and subject were investigated. We found that the subject effect was significant for all computed sleep metrics. Furthermore, the equipment did not show any statistical significant effect on any of the sleep metrics. Discussion: These results corroborate that generic ear-EEG is a promising alternative to the gold standard PSG for sleep stage monitoring. This will allow sleep stage monitoring to be performed in a less obtrusive way and over longer periods of time, thereby enabling diagnosis and treatment of diseases with associated sleep disorders.

Disruption of Sleep Microarchitecture Is a Sensitive and Early Marker of Parkinson's Disease.

BACKGROUND: Although sleep disturbances are highly prevalent in patients with Parkinson's disease, sleep macroarchitecture metrics show only minor changes. OBJECTIVE: To assess alterations of the cyclic alternating pattern (CAP) as a critical feature of sleep microarchitecture in patients with prodromal, recent, and established Parkinson's disease. METHODS: We evaluated overnight polysomnography for classic sleep macroarchitecture and CAP metrics in 68 patients at various disease stages and compared results to 22 age- and sex-matched controls. RESULTS: Already at the prodromal stage, patients showed a significantly reduced CAP rate as a central characteristic of sleep microarchitecture. Temporal characteristics of CAP showed a gradual change over disease stages and correlated with motor performance. In contrast, the sleep macroarchitecture metrics did not differ between groups. CONCLUSION: Data suggest that alterations of sleep microarchitecture are an early and more sensitive characteristic of Parkinson's disease than changes in sleep macroarchitecture.

Imaging progressive peripheral and central dysfunction in isolated REM sleep behaviour disorder after 3 years of follow-up.

INTRODUCTION: Most patients with isolated rapid eye movement sleep behaviour disorder (iRBD) convert to Parkinson's disease (PD), dementia with Lewy bodies, or multiple system atrophy within 15 years of diagnosis. Furthermore, iRBD patients develop non-motor symptoms similar to those of manifest PD patients and display dysfunction of the sympathetic and parasympathetic nervous system, comparable to that seen in PD. However, progression rates of autonomic dysfunction in iRBD have not been studied with objective measures in detail, which is the aim of this study. METHODS: Twenty-two iRBD patients were included at baseline and 14 participated in follow-up after 3 years. Colonic transit time (CTT) was examined using radio opaque markers, colonic volume was defined on abdominal computed tomography (CT) scans, Iodine-123-metaiodobenzylguanidine ([123I]MIBG) scintigraphy was performed to assess cardiac sympathetic innervation, and 3,4-dihydroxy-6-(18F) fluoro-l-phenylalanine ([18F]FDOPA) positron emission tomography (PET) scan determined nigrostriatal dopamine storage capacity. All examinations were performed at baseline and after 3 years. RESULTS: iRBD patients displayed increased CTT (p = 0.001) and colonic volume (p = 0.01) at follow-up compared to baseline. Furthermore, [123I]MIBG uptake and [18F]FDOPA uptake showed progressive reductions at follow-up (p = 0.02 and p = 0.002, respectively). No correlations were seen between changes in intestinal or cardiac measurements and dopaminergic function. CONCLUSION: Using objective markers, the present study documented that intestinal dysfunction and cardiac sympathetic degeneration worsen in the majority of iRBD patients over a 3-year period. The absent correlation between these markers and nigrostriatal dopaminergic dysfunction suggests that progressive gastrointestinal and cardiac dysfunction in iRBD is caused mainly by non-dopaminergic mechanisms.

A candidate gene study of serotonergic pathway genes and pain relief during treatment with escitalopram in patients with neuropathic pain shows significant association to serotonin receptor2C (HTR2C).

PURPOSE: Previous studies have shown that a small fraction of patients with peripheral neuropathic pain experiences >50% pain relief during treatment with selective serotonin reuptake inhibitors (SSRIs), whereas most patients have no or only slight relief. The aim of this study was to investigate the association between polymorphisms in genes involved in the serotonergic pathway and the effect of escitalopram on peripheral neuropathic pain. METHODS: We genotyped 34 participants from a placebo-controlled trial of escitalopram in peripheral neuropathic pain for polymorphisms in five genes: the serotonin receptor 2A (HTR2A) gene, the serotonin receptor 2C (HTR2C) gene, the ABCB1 gene encoding for the P-glycoprotein, the CYP2C19 gene, and the serotonin transporter gene (SLC6A4). RESULTS: The SNP rs6318 (Cys23Ser) in the HTR2C gene showed significant association with treatment response in men (p = 0.047), with 75% carrying the C allele being responders. The same tendency was seen in women. Similarly, carriership of the C allele at rs6318 was associated with better pain relief during treatment with escitalopram [odds ratio (OR) 15.5, p = 0.014)] Furthermore, there was a tendency of better relief with increasing number of short alleles for the 5-HTTLPR polymorphism of the serotonin transporter (OR 5.7, p = 0.057). None of the other polymorphisms showed a significant association with treatment response to escitalopram. CONCLUSION: This study indicates that variation in the HTR2C gene is associated to the pain-relieving effect of escitalopram in patients with painful polyneuropathy.

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.

A Screening-Based Method for Identifying Patients with REM Sleep Behaviour Disorder in a Danish Community Setting.

Isolated REM sleep behaviour disorder (iRBD) is a predictive marker of prodromal Lewy body disease. iRBD prevalence in the general population is around 1%, but it remains under-diagnosed, even though symptoms are alleviated by medication. We developed a population screening strategy and identified 16 iRBD patients by conducting telephone interviews and polysomnography examinations. We compared our population-screened cohort with sleep-center referred patients and found higher MoCA scores and lower MDS-UPDRS-III scores in our patients. In conclusion, screening can be used to identify iRBD patients in a cost-effective manner with the benefit of identifying patients at a very early disease stage.

Factors with impact on magnitude of the placebo response in randomized, controlled, cross-over trials in peripheral neuropathic pain.

The presence and magnitude of placebo responses is important for the outcome in clinical trials of analgesics. This explorative study aimed at identifying patients and trial-specific factors with impact on this response in randomized, controlled, cross-over trials in peripheral neuropathic pain. Data were derived from 7 trials and included observations on pinprick hyperalgesia, allodynia, and pain on repetitive stimulation. The studies were all performed by the same collaboration group in Denmark. Pain was rated daily using numeric 0 to 10 point rating scales (NRS) and placebo response was calculated as the difference in weekly average or median numeric rating scale from baseline to the last week of treatment. A clinically meaningful placebo response was defined as more than 30% reduction of pain on placebo. In 318 individual observations, the response was on average small (0.17 points, range -4.5 to 6). There was no significant impact on size of placebo response of trial-specific factors such as treatment sequence and chance of having placebo treatment in each period or of the patient-specific factors age, sensory signs, and pain symptoms. The findings were similar in patients having placebo in the first treatment period. There was no marked difference between patients with (n = 43) and without (n = 275) a clinically meaningful placebo response with respect to the patient-specific factors including frequency of sensory signs and symptoms. In conclusion, this study on cross-over trials in peripheral neuropathic pain found no robust impact of trial and patient-specific factors on the placebo response.

Cortical cholinergic dysfunction correlates with microglial activation in the substantia innominata in REM sleep behavior disorder.

INTRODUCTION: In vivo PET studies in patients with isolated REM sleep behavior disorder (iRBD) have shown presence of neuroinflammation (microglial activation) in the substantia nigra, and reduced cortical acetylcholinesterase activity, suggestive of cholinergic dysfunction, that was more widespread in patients with poorer cognitive performances. This study aimed to explore whether reduced cortical acetylcholinesterase activity in iRBD is linked to microglial activation in the substantia innominata (SI), the major source of cholinergic input to the cortex. METHODS: We used 11C(R)-PK11195 and 11C-Donepezil PET to assess levels of activated microglia and cholinergic function, respectively, in 19 iRBD patients. 11C(R)-PK11195 binding potential (BPND) and 11C-Donepezil distribution volume ratio (DVR) values were correlated using the Pearson statistic. RESULTS: We found that a lower cortical 11C-Donepezil DVR correlated with a higher 11C(R)-PK11195 BPND in the SI (r = -0.48, p = 0.04). At a voxel level, the strongest negative correlations were found in the frontal and temporal lobes. CONCLUSION: Our results suggest that reduced cortical acetylcholinesterase activity observed in our iRBD patients could be linked to the occurrence of neuroinflammation in the SI. Early modulation of microglial activation might therefore preserve cortical cholinergic functions in these patients.