Progression of clinical markers in prodromal Parkinson's disease and dementia with Lewy bodies: a multicentre study.

The neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson's disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson's disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson's disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.

Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson's patients.

Synucleinopathies such as Parkinson's disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

Widening the Spectrum of Risk Factors, Comorbidities, and Prodromal Features of Parkinson Disease.

Importance: The prodromal phase of Parkinson disease (PD) may last for more than 10 years. Recognition of the spectrum and occurrence of risk factors, comorbidities, and prodromal features of PD can increase understanding of the causes and development of the disease and help identify individuals at risk. Objective: To identify the association of a subsequent diagnosis of PD with a range of risk factors and prodromal features, including lifestyle factors, comorbidities, and potential extracerebral manifestations of PD. Design, Setting, and Participants: This was a case-control study using insurance claims of outpatient consultations of patients with German statutory health insurance between January 1, 2011, and December 31, 2020. Included were patients with incident diagnosis of PD without a previous diagnosis of parkinsonism or dementia and controls matched 1:2 for age, sex, region, and earliest year of outpatient encounter. Exposures: Exposures were selected based on previous systematic reviews, case-control and cohort studies reporting on risk factors, comorbidities, and prodromal features of PD. Main Outcomes and Measures: Previously postulated risk factors and prodromal features of PD, using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) coding. Results: A total of 138 345 patients with incident PD (mean [SD] age, 75.1 [9.8] years; 73 720 male [53.3%]) and 276 690 matched controls (mean [SD] age, 75.1 (9.8) years; 147 440 male [53.3%]) were identified. Study participants were followed up for a mean (SD) of 6.0 (2.0) years. Consistent with previous reports, risk factors and prodromal features associated with PD included traumatic brain injury, odds ratio (OR), 1.62; 95% CI, 1.36-1.92; alcohol misuse, OR, 1.32; 95% CI, 1.21-1.44; hypertension, OR, 1.29; 95% CI, 1.26-1.31; anosmia, OR, 2.16; 95% CI, 1.59-2.93; and parasomnias (including RBD), OR, 1.62; 95% CI, 1.42-1.84. In addition, there were associations with restless legs syndrome (OR, 4.19; 95% CI, 3.91-4.50), sleep apnea (OR, 1.45; 95% CI, 1.37-1.54), epilepsy (OR, 2.26; 95% CI, 2.07-2.46), migraine (OR, 1.21; 95% CI, 1.12-1.29), bipolar disorder (OR, 3.81; 95% CI, 3.11-4.67), and schizophrenia (OR, 4.48; 95% CI, 3.82-5.25). The following diagnoses were also found to be associated with PD: sensory impairments beyond anosmia, such as hearing loss (OR, 1.14; 95% CI, 1.09-1.20) and changes of skin sensation (OR, 1.31; 95% CI, 1.21-1.43). There were also positive associations with skin disorders (eg, seborrheic dermatitis, OR, 1.30; 95% CI, 1.15-1.46; psoriasis, OR, 1.13; 95% CI, 1.05-1.21), gastrointestinal disorders (eg, gastroesophageal reflux, OR, 1.29; 95% CI, 1.25-1.33; gastritis, OR, 1.28; 95% CI, 1.24-1.33), conditions with a potential inflammatory component (eg, seronegative osteoarthritis, OR, 1.21; 95% CI, 1.03-1.43), and diabetes types 1 (OR, 1.32; 95% CI, 1.21-1.43) and 2 (OR, 1.24; 95% CI, 1.20-1.27). Associations even 5 to 10 years before diagnosis included tremor (odds ratio [OR], 4.49; 95% CI, 3.98-5.06), restless legs syndrome (OR, 3.73; 95% CI, 3.39-4.09), bipolar disorder (OR, 3.80; 95% CI, 2.82-5.14), and schizophrenia (OR, 4.00; 95% CI, 3.31-4.85). Conclusions and Relevance: Results of this case-control study suggest that the associations found between PD and certain risk factors, comorbidities, and prodromal symptoms in a representative population may reflect possible early extrastriatal and extracerebral pathology of PD. This may be due to shared genetic risk with PD, medication exposure, or direct causation, or represent pathophysiologically relevant factors contributing to the pathogenesis of PD.

Management of Sleep Disturbances in Parkinson's Disease.

Parkinson's disease (PD) is defined by its motor symptoms rigidity, tremor, and akinesia. However, non-motor symptoms, particularly autonomic disorders and sleep disturbances, occur frequently in PD causing equivalent or even greater discomfort than motor symptoms effectively decreasing quality of life in patients and caregivers. Most common sleep disturbances in PD are insomnia, sleep disordered breathing, excessive daytime sleepiness, REM sleep behavior disorder, and sleep-related movement disorders such as restless legs syndrome. Despite their high prevalence, therapeutic options in the in- and outpatient setting are limited, partly due to lack of scientific evidence. The importance of sleep disturbances in neurodegenerative diseases has been further emphasized by recent evidence indicating a bidirectional relationship between neurodegeneration and sleep. A more profound insight into the underlying pathophysiological mechanisms intertwining sleep and neurodegeneration might lead to unique and individually tailored disease modifying or even neuroprotective therapeutic options in the long run. Therefore, current evidence concerning the management of sleep disturbances in PD will be discussed with the aim of providing a substantiated scaffolding for clinical decisions in long-term PD therapy.

Affection of Respiratory Muscles in ALS and SMA.

Respiratory dysfunction is a common cause of morbidity and mortality in motor neuron disease (MND). However, classical volitional measures of respiratory function in these patients are impeded by, e.g., bulbar paralysis or progressive disability. Diaphragm ultrasound imaging might be a valuable tool for assessing respiratory impairment, albeit different ultrasound measures have not been systematically investigated in adult MND patients and, in particular, have not yet been comparatively applied in adult patients with amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). We hypothesized that in contrast to ALS patients, adult SMA patients show a relative sparing of diaphragm function. We retrospectively analyzed diaphragm ultrasound imaging data of 40 patients with ALS and 23 patients with SMA in comparison to a multitude of established parameters of respiratory function. Indeed, ALS patients showed more severe diaphragm dysfunction than adult SMA patients, however, diaphragm dysfunction was also common in adult SMA patients. Notably, dynamic measures of diaphragm function rather than thickness measures were impaired in ALS compared to SMA. Thus, diaphragm ultrasound imaging might be a useful tool to evaluate respiratory dysfunction in adult MND patients. Future larger and prospective studies are needed to validate our initial findings.

Functional MAOB Gene Intron 13 Polymorphism Predicts Dyskinesia in Parkinson's Disease.

Identification of individual risk factors for motor complications in Parkinson's disease (PD) can help to guide personalised medical treatment, particularly since treatment options are still limited. To determine whether common functional gene polymorphisms in the dopamine metabolism predict the onset of motor complications in PD, we performed a retrospective, observer-blinded follow-up study of 30 PD patients who underwent genotyping of dopa-decarboxylase (DDC; rs921451), monoamine oxidase B (MAOB; rs1799836), catechol-O-methyltransferase (COMT; rs4680), and dopamine transporter (DAT; variable number tandem repeat) polymorphisms. Onset of wearing-off and dyskinesias was determined by blinded clinical assessments. Predictive values of genotypes for motor complications were evaluated using Cox proportional hazard models. During a median follow-up time of 11.6 years, 23 (77%) of 30 PD patients developed wearing-off, 16 (53%) dyskinesias, and 23 (77%) any motor complication. The MAOB (rs1799836) polymorphism predicted development of dyskinesias with MAOB CC/(C)/CT genotypes (resulting in low/intermediate brain enzyme activity) being associated with lower hazard ratios (unadjusted HR [95% CI]: 0.264 [0.089-0.787]; p=0.012; adjusted HR [95% CI]: 0.142 [0.039-0.520]; p=0.003) than MAOB TT/(T) genotypes (resulting in high brain enzyme activity). DDC (rs921451), COMT (rs4680), and DAT (VNTR) polymorphisms were not predictive of motor complications. Together, the MAOB (rs1799836) polymorphism predicts the development of dyskinesias in PD patients. Our results need confirmation in larger cohorts. If confirmed, individual assessment of this polymorphism might be helpful for early risk stratification and could comprise a step towards patient-tailored therapeutic strategies to prevent or delay motor complications in the course of PD.

An algorithm for actigraphy-based sleep/wake scoring: Comparison with polysomnography.

OBJECTIVE: To evaluate the accuracy of actigraphy against polysomnography (PSG) as gold standard using a newly developed algorithm for sleep/wake discrimination that explicitly models the temporal structure of sleep. METHODS: PSG was recorded in 11 men and 9 women (age 71.1±5.0) to evaluate suspected neuropsychiatric sleep disturbances. Simultaneously, wrist actigraphy was recorded, from which 37 features were computed for each 1-min epoch. We compared prediction of PSG-derived sleep/wake states for each of these features between our newly developed algorithm, and four state-of-the-art algorithms. The algorithms were evaluated using a leave-one-subject out cross validation. RESULTS: The new algorithm classified 84.9% of sleep epochs (sensitivity) and 74.2% of wake epochs correctly (specificity), leading to a sleep/wake scoring accuracy of 79.0%. Four out of five sleep parameters were estimated more accurately by the new algorithm than by state-of-the-art algorithms. CONCLUSION: The proposed algorithm achieved a significantly higher specificity than state-of-the-art algorithm, with only minor decrease in sensitivity for patients with sleep disorders. We assume this reflects the capability of the algorithm to explicitly model sleep architecture. SIGNIFICANCE: The unobtrusive assessment of sleep/wake cycles is particularly relevant for patients with neuropsychiatric diseases that are associated with sleep disturbances, such as depression or dementia.

Relation of retinal and hippocampal thickness in patients with amnestic mild cognitive impairment and healthy controls.

OBJECTIVE: Investigating retinal thickness may complement existing biological markers for dementia and other neurodegenerative diseases. Although retinal thinning is predictive for cognitive decline, it remains to be investigated if and how this feature aligns with neurodegeneration elsewhere in the brain, specifically in early disease stages. METHODS: Using optical coherence tomography and magnetic resonance imaging, we examined retinal thickness as well as hippocampal structure in patients with amnestic mild cognitive impairment and healthy controls. RESULTS: The groups did not differ in hippocampal and retinal thickness measures. However, we detected a correlation of peripapillary retinal nerve fiber layer thickness and hippocampal thickness in healthy people but not in cognitively impaired patients. The ratio of hippocampus to retina thickness was significantly smaller in patients with mild cognitive impairment and correlated positively with cognitive performance. CONCLUSIONS: Different temporal trajectories of neurodegeneration may disrupt transregional brain structure associations in patients with amnestic mild cognitive impairment.

Insomnia in neurological diseases.

Insomnia is defined as difficulties of initiating and maintaining sleep, early awakening and poor subjective sleep quality despite adequate opportunity and circumstances for sleep with impairment of daytime performance. These components of insomnia - namely persistent sleep difficulties despite of adequate sleep opportunity resulting in daytime dysfunction - appear secondary or co-morbid to neurological diseases. Comorbid insomnia originates from neurodegenerative, inflammatory, traumatic or ischemic changes in sleep regulating brainstem and hypothalamic nuclei with consecutive changes of neurotransmitters. Symptoms of neurological disorders (i.e motor deficits), co-morbidities (i.e. pain, depression, anxiety) and some disease-specific pharmaceuticals may cause insomnia and/or other sleep problems.This guideline focuses on insomnias in headaches, neurodegenerative movement disorders, multiple sclerosis, traumatic brain injury, epilepsies, stroke, neuromuscular disease and dementia.The most important new recommendations are: Cognitive behavioral therapy (CBTi) is recommended to treat acute and chronic insomnia in headache patients. Insomnia is one of the most frequent sleep complaints in neurodegenerative movement disorders. Patients may benefit from CBTi, antidepressants (trazodone, doxepin), melatonin and gaba-agonists. Insomnia is a frequent precursor of MS symptoms by up to 10 years. CBTi is recommended in patients with MS, traumatic brain injury and. Melatonin may improve insomnia symptoms in children with epilepsies. Patients with insomnia after stroke can be treated with benzodiazepine receptor agonists and sedating antidepressants. For patients with dementia suffering from insomnia trazodone, light therapy and physical exercise are recommended.

Autotitrating Bilevel Positive Airway Pressure in Large Vessel Steno-Occlusive Stroke Patients With Suspected Sleep Apnea: A Multicenter Randomized Controlled Study.

Background: We hypothesized that autotitrating bilevel positive airway pressure (auto-BPAP) favorably affects short-term clinical outcomes in hyperacute ischemic stroke. Methods: In a multicenter, randomized, controlled trial patients with large vessel steno-occlusive stroke and clinically suspected sleep apnea were allocated to auto-BPAP or standard stroke care alone. Auto-BPAP was initiated within 24 h from stroke onset and performed over 48 h during diurnal and nocturnal sleep. Sleep apnea was assessed using cardiorespiratory polygraphy. Primary endpoint was early neurological improvement on National Institutes of Health Stroke Scale (NIHSS) score at 72 h. Safety and tolerability of BPAP, functional independence [modified Rankin Scale (mRS) 0-2], stroke recurrence, and mortality at 90 days were assessed. Results: Due to low recruitment, the trial was prematurely stopped after 24 patients had been randomized (auto-BPAP, n = 14; control, n = 10): median baseline NIHSS 13 (5.5-18), 88% large vessel occlusion, and 12% large vessel stenosis. Polygraphy confirmed sleep apnea in 64% of auto-BPAP and 88% of control patients (p = 0.34). Adherence to auto-BPAP was achieved by 9 of the 14 (64%) patients. Between auto-BPAP and control patients, no differences were observed in early neurological improvement (median NIHSS change: -2.0, IQR = 7 points vs. -0.5, IQR = 3 points), 90 days functional independence (21 vs. 30%, p = 0.67), stroke recurrence (0 vs. 20%, p = 0.16), and death (14 vs. 20%, p = 1.0). No safety concerns were identified. Conclusions: In this prematurely terminated trial, auto-BPAP was safe but did not show an effect on short-term clinical outcomes in selected ischemic stroke patients. Its tolerability, however, may be limited in hyperacute stroke care and needs to be improved before larger trials are conducted. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT01812993.

Biomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder.

Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving α-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal α-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest α-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of α-synucleinopathy patients with isolated RBD might develop.

Asymmetry of Periodic Leg Movements in Sleep (PLMS) in Parkinson's Disease.

BACKGROUND: Periodic limb movements in sleep (PLMS) are repetitive movements usually of the legs strongly associated with Restless-legs syndrome (RLS), which appear more frequently in males, older age and other sleep disturbances, such as sleep-disordered breathing (SDB). Patients with Parkinson's disease (PD) suffer from various sleep disturbances including REM sleep behavior disorder, RLS and PLMS. Although a dopaminergic pathophysiology of PLMS is discussed, no systematic data on PLMS side-to-side distribution in PD and its correlation with asymmetry of motor symptoms are available. OBJECTIVE: This study aimed at elucidating PLMS asymmetry in correlation to that of motor symptoms in PD compared to SDB and RLS. METHODS: Cross-sectional, retrospective analysis of two polysomnography (PSG) recordings per patient scoring PLMS separately for both legs. RESULTS: Of 105 patients (44 PD, 44 age- and sex-matched SDB and 17 RLS patients) PLMS measures (number of PLM, PLM-Index, PLM-arousal index) showed significant side-to-side differences in all disease entities in both PSGs (P < 0.001; Wilcoxon rank test). PLM-Index asymmetry (PLM-I difference of >5/h between both sides) was observed less frequently in PD (34% of patients) compared to RLS (77% , P < 0.05) and SDB (59% , P < 0.05; χ2 test). In asymmetric PD patients, predominant side of PLMS was more stable than in SDB and RLS comparing the two PSGs, but we did not detect an agreement between PLMS predominant side with that of motor symptoms in PD patients. CONCLUSIONS: Only the minority of PD patients shows asymmetric PLMS distribution with relatively high night-to-night stability but no correlation with motor symptom asymmetry.

Sleep Disturbances and Sleep Disordered Breathing Impair Cognitive Performance in Parkinson's Disease.

BACKGROUND: Sleep disturbances and impairment of cognitive function are among the most frequent non-motor symptoms in Parkinson's disease (PD) with negative implications on quality of life of patients and caregivers. Despite the fact that sleep disturbances are a major issue in PD patients, only limited data are available regarding interactions of sleep disturbances and cognitive performance. OBJECTIVE: This post hoc analysis of the RaSPar trial was therefore designed to further elucidate sleep disturbances and their impact on cognition in PD. METHODS: Twenty-six PD patients with sleep disturbances were evaluated thoroughly including assessments of patients' subjective and objective sleep quality by interview, questionnaires, and polysomnography (PSG). Cognitive performance was assessed by Parkinson Neuropsychometric Dementia Assessment (PANDA) and Test of Attentional Performance (TAP), and associations of sleep and cognitive function were evaluated. RESULTS: We did not detect differences in cognitive performance between patients with and without rapid eye movement (REM) sleep behavior disorder (RBD). Instead, cognitive impairment, particularly affecting cognitive domains attention, executive function/working memory, and semantic memory, was associated with impaired PSG-measured sleep quality (e.g., sleep efficiency) and sleep disordered breathing (SDB) (Apnea-Hypopnea Index > 5/h). Global cognitive performance was decreased in patients with SDB (PANDA score 23.2 ± 3.5 vs. 26.9 ± 2.2, P = 0.020, unpaired two-sided t-test). CONCLUSION: Sleep apnea and other sleep disturbances impair cognitive performance in PD and should be evaluated in routine care, and treatment options such as continuous airway pressure therapy should be considered.

Thalamic GABA may modulate cognitive control in restless legs syndrome.

The restless legs syndrome (RLS) has repeatedly, but not exclusively, been associated with functional thalamic changes as well as changes in GABAergic neurotransmission. This has been linked to the well-known sensory-motor symptoms, but it has never been investigated whether those factors also account for potential cognitive changes in RLS, even though they are known to play an important role for cognitive control. To investigate the potential relationship between thalamic GABA concentrations and cognitive control in n = 25 RLS patients; a neuropsychological experimental paradigm was used in combination with magnetic resonance spectroscopy (MRS). Compared to n = 31 healthy controls, RLS patients displayed reduced cognitive control capacities, which were most likely based on working memory deficits. On the neurobiochemical level, (relatively) elevated thalamic GABA levels attenuated control deficits only in the RLS group, even though there were no group differences with respect to overall GABA levels. Given that RLS patients are known to display thalamic hyperactivity and associated thalamic hypoconnectivity, (relatively) higher GABA levels may have helped RLS patients to "compensate" for this pathological factor. Our findings specify the functional relevance of thalamic GABAergic neurotransmission for cognition in RLS, even though changes in GABAergic neurotransmission might not be the ultimate cause of control deficits.

Putaminal Dopamine Turnover in de novo Parkinson's Disease Predicts Later Neuropsychiatric Fluctuations but Not Other Major Health Outcomes.

BACKGROUND AND OBJECTIVE: To investigate the predictive value of striatal dopamine turnover in patients with de novo Parkinson's disease (PD) for later occurrence of major non-motor health outcomes. METHODS: This retrospective, observer-blinded cohort study followed up 29 patients with de novo PD for a median of 10.7 years, who completed 18Fluorodopa PET imaging to measure striatal effective distribution volume ratio (EDVR, inverse of dopamine turnover) prior to antiparkinsonian treatment. Outcomes were assessed with a battery of non-motor, health-related quality-of-life and non-motor fluctuation (WOQ-19) measures and survival. RESULTS: During follow-up, 52% of patients developed wearing-off, 43% neuropsychiatric fluctuations, 35% sensory fluctuations, 32% dementia, 46% depression, 30% psychosis, and PD-related mortality was 26%. Patients with wearing-off and neuropsychiatric fluctuations showed significantly lower baseline EDVR (higher dopamine turnover) in the putamen but not in the caudate nucleus than those without these fluctuations. Consistently, baseline EDVR in the putamen predicted development of wearing-off and neuropsychiatric fluctuations with a lower risk with higher EDVR (lower dopamine turnover), whereas EDVR in caudate nucleus did not correlate with these fluctuations. No relationships were observed between baseline PET measures and the presence of other major health outcomes including survival. CONCLUSIONS: Lower putaminal dopamine turnover in de novo PD is associated with reduced risk for later neuropsychiatric fluctuations comprising a disease-intrinsic predisposing factor for their development, similar as reported for levodopa-induced motor complications. Striatal (putaminal/caudate) dopamine turnover is not predictive for other long-term major health outcomes. These results should be treated as hypothesis generating and require confirmation.