Monitoring of 30 marker candidates in early Parkinson disease as progression markers.

OBJECTIVE: This was a longitudinal single-center cohort study to comprehensively explore multimodal progression markers for Parkinson disease (PD) in patients with recently diagnosed PD (n = 123) and age-matched, neurologically healthy controls (HC; n = 106). METHODS: Thirty tests at baseline and after 24 months covered nonmotor symptoms (NMS), cognitive function, and REM sleep behavior disorder (RBD) by polysomnography (PSG), voxel-based morphometry (VBM) of the brain by MRI, and CSF markers. Linear mixed-effect models were used to estimate differences of rates of change and to provide standardized effect sizes (d) with 95% confidence intervals (CI). RESULTS: A composite panel of 10 informative markers was identified. Significant relative worsening (PD vs HC) was seen with the following markers: the Unified Parkinson's Disease Rating Scale I (d 0.39; CI 0.09-0.70), the Autonomic Scale for Outcomes in Parkinson's Disease (d 0.25; CI 0.06-0.46), the Epworth Sleepiness Scale (d 0.47; CI 0.24-0.71), the RBD Screening Questionnaire (d 0.44; CI 0.25-0.64), and RBD by PSG (d 0.37; CI 0.19-0.55) as well as VBM units of cortical gray matter (d -0.2; CI -0.3 to -0.09) and hippocampus (d -0.15; CI -0.27 to -0.03). Markers with a relative improvement included the Nonmotor Symptom (Severity) Scale (d -0.19; CI -0.36 to -0.02) and 2 depression scales (Beck Depression Inventory d -0.18; CI -0.36 to 0; Montgomery-Åsberg Depression Rating Scale d -0.26; CI -0.47 to -0.04). Unexpectedly, cognitive measures and select laboratory markers were not significantly changed in PD vs HC participants. CONCLUSIONS: Current CSF biomarkers and cognitive scales do not represent useful progression markers. However, sleep and imaging measures, and to some extent NMS, assessed using adequate scales, may be more informative markers to quantify progression.

Restless Legs Syndrome: Psychiatric Comorbidities Are More Important Than Neuroticism.

Restless legs syndrome (RLS) is often associated with psychopathological symptoms. We compared psychiatric diagnoses, psychological complaints, sleep and personality traits in RLS patients and a control group The RLS patients also answered the IRLS, RLS-6, and QoL-RLS. The RLS patients showed more depressive disorders, psychopathological symptoms, and lower well-being than controls, but no differences in personality traits. The slightly, but not significantly, higher neuroticism found in RLS patients can be explained by the higher rates of depression among the patients. It is advisable to screen RLS patients for psychiatric comorbidities. The design using a matched control group without sleep disorders limits the conclusions that can be drawn regarding the frequency of psychiatric diagnoses and controls with sleep problems.

Rapid eye movement sleep behavioral events: a new marker for neurodegeneration in early Parkinson disease?

OBJECTIVE: To analyze potential markers in sleep for early recognition of neurodegenerative disease in newly diagnosed, unmedicated patients with Parkinson disease (PD) compared to controls. METHODS: Videopolysomnography (vPSG) was available in 158 newly diagnosed, unmedicated patients with PD and 110 age-, sex-, and education-matched healthy controls (HC). Rapid eye movement (REM) sleep was analyzed for REM without atonia (RWA) and studied by review of time-synchronized video. Motor behaviors and/or vocalizations in REM sleep with a purposeful component other than comfort moves were identified as REM sleep behavioral events (RBE). Two or more events had to be present to be classified as "RBE positive." RBE subjects included rapid eye movement sleep behavior disorder (RBD) and non-RBD subjects based on the presence or absence of RWA > 18.2%. RESULTS: RBE were detected in 81 of 158 patients with de novo PD (51%) and 17 of 110 HC (15%) (P < 0.001). RBD was identified in 40/81 RBE-positive patients with PD (25% of all PD patients) and 2 of 17 RBE-positive HC (2% of all controls). RBE-positive patients showed no specific motor or neuropsychological features compared to RBE-negative patients. Patients with PD and HC with RBE had more REM sleep (P = 0.002) and a higher periodic leg movements in sleep index (P = 0.022) compared to subjects without RBE. CONCLUSION: This first description of REM sleep behavioral events (RBE) shows it occurs more frequently in patients with de novo Parkinson disease (PD) than in healthy controls and may be an early sign of neurodegeneration and precede rapid eye movement sleep behavior disorder (RBD). There is no specific phenotype of PD associated with newly defined RBE or RBD at this early stage.

Nonmotor and diagnostic findings in subjects with de novo Parkinson disease of the DeNoPa cohort.

OBJECTIVE: To determine nonmotor signs (NMS) and evaluate the utility of several diagnostic tools in patients with de novo Parkinson disease (PD). METHODS: This is a large single-center study of the DeNoPa cohort, including frequency-matched healthy controls. This study covers motor signs, NMS, and a combination of diagnostic tests including olfactory testing, transcranial sonography of substantia nigra (TCS), and polysomnography (PSG). We report the frequency and characteristics of NMS and the outcomes of nonmotor tests at the time of diagnosis. RESULTS: Cross-sectional analyses of baseline investigations identified significant differences in the NMS Questionnaire (NMSQuest) and the Scopa-AUT Gastrointestinal score in 159 drug-naïve PD patients vs 110 controls. In addition, patients with PD showed reduced olfactory function, hyperechogenicity on TCS, and higher frequency of REM sleep behavior disorder (RBD). In exploring predictive markers, we found that the combination of several investigations, i.e., the NMSQuest, Scopa-AUT Gastrointestinal score, and Smell Identification Test reached an area under the receiver operating characteristic curve (AUC) of 0.913 (95% confidence interval [CI] 0.878-0.948). With the addition of serum cholesterol and mean heart rate values, the AUC value reached 0.919 (95% CI 886-0.953); when TCS and PSG were added, the AUC increased to 0.963 (95% CI 0.943-0.982). CONCLUSIONS: We show feasibility and utility of standardized data acquisition in a large, single-center cohort of patients with de novo PD and matched healthy controls. The baseline results from our prospective investigations reached a value of >0.9 sensitivity and specificity for biological markers when we added routine laboratory investigations and quantified nonmotor features including sleep.

Total CSF α-synuclein is lower in de novo Parkinson patients than in healthy subjects.

Several studies demonstrated reduced CSF α-synuclein values in patients with advanced Parkinson's disease (PD). Values in drug-naïve PD subjects and healthy controls (HC) have not yet been reported. We measured CSF values including α-synuclein in a cohort of 78 previously untreated PD patients and 48 HC subjects. Measurements of total α-synuclein concentrations were performed using two independently operated immunoassays, i.e., one academia-based and previously validated (ELISA 1), the other industry-based, renewable and commercially available (ELISA 2). Mean values for CSF α-synuclein were significantly lower in de novo PD patients when compared to HC subjects, as demonstrated by both assays (ELISA 1, p=0.049; ELISA 2, p=0.005; combined, p=0.002). Using the renewable ELISA 2, CSF α-synuclein concentrations of 1884.31 pg/ml or less showed a sensitivity of 0.91 and a specificity of 0.25 for the diagnosis of Parkinson's disease. The corresponding area-under-the-curve value was 0.65 (confidence interval, 0.554-0.750), which was statistically significant (p=0.004). Total CSF α-synuclein is reduced early in the course of Parkinson's disease, as measured by two independent ELISA platforms at the time of enrolment, and this reduction appears independent from drug treatment. Follow-up investigations will determine the usefulness of CSF α-synuclein values as markers of progression in individual subjects.

Age, drugs, or disease: what alters the macrostructure of sleep in Parkinson's disease?

OBJECTIVE: To describe the alterations in the macrostructure of sleep in a large cohort of sleep-disturbed patients with Parkinson's disease (PD) and investigate influencing factors. METHODS: A cohort of sleep-disturbed but otherwise unselected PD patients (n=351) was investigated with video-supported polysomnography. We analyzed the influence of age, disease duration, disease severity, and dopaminergic medication on subjective sleep perception, sleep efficiency, the amount of slow wave sleep, awakenings, periodic leg movements in sleep (PLMS), and REM sleep behavior disorder (RBD). RESULTS: Sleep efficiency and slow wave sleep decreased with age (p=0.003 and p=0.041, respectively). The number of awakenings and the frequency of RBD increased with age (p=0.028 and p=0.006, respectively). Higher Hoehn & Yahr stages were associated with more PLMS (p=0.017). A higher daily dose of levodopa corresponded to more RBD (p<0.001). Neither disease duration nor levodopa dosage had any influence on sleep efficiency, slow wave sleep, awakenings, or PLMS. Dopamine agonists increased awakenings (p<0.001) and lowered PLMS (p<0.001). Subjective sleep perception was not influenced by any of the factors analyzed. The only path model that could be replicated identified disease severity and dopamine agonists as interdependent factors influencing awakenings and PLMS. CONCLUSION: Age leads to less sleep and a higher risk for RBD, and disease severity increases motor phenomena such as PLMS; dopamine agonists reduce PLMS but increase awakenings. No single factor analyzed influenced subjective sleep perception in this cohort of sleep disturbed PD patients.

α-Synuclein in human cerebrospinal fluid is principally derived from neurons of the central nervous system.

The source of Parkinson disease-linked α-synuclein (aSyn) in human cerebrospinal fluid (CSF) remains unknown. We decided to measure the concentration of aSyn and its gradient in human CSF specimens and compared it with serum to explore its origin. We correlated aSyn concentrations in CSF versus serum (Q(aSyn)) to the albumin quotient (Q(albumin)) to evaluate its relation to blood-CSF barrier function. We also compared aSyn with several other CSF constituents of either central or peripheral sources (or both) including albumin, neuron-specific enolase, ß-trace protein and total protein content. Finally, we examined whether aSyn is present within the structures of the choroid plexus (CP). We observed that Q(aSyn) did not rise or fall with Q(albumin) values, a relative measure of blood-CSF barrier integrity. In our CSF gradient analyses, aSyn levels decreased slightly from rostral to caudal fractions, in parallel to the recorded changes for neuron-specific enolase; the opposite trend was recorded for total protein, albumin and ß-trace protein. The latter showed higher concentrations in caudal CSF fractions due to the diffusion-mediated transfer of proteins from blood and leptomeninges into CSF in the lower regions of the spine. In postmortem sections of human brain, we detected highly variable aSyn reactivity within the epithelial cell layer of CP in patients diagnosed with a range of neurological diseases; however, in sections of mice that express only human SNCA alleles (and in those without any Snca gene expression), we detected no aSyn signal in the epithelial cells of the CP. We conclude from these complementary results that despite its higher levels in peripheral blood products, neurons of the brain and spinal cord represent the principal source of aSyn in human CSF.

Associated factors for REM sleep behavior disorder in Parkinson disease.

OBJECTIVE: To investigate the frequency, phenomenology, and associated risk factors of REM sleep behavior disorder (RBD) in Parkinson disease (PD). METHODS: An unselected cohort of sleep-disturbed patients with PD (n=457) was investigated with video-supported polysomnography. We determined the frequency of RBD and analyzed the influence of age, clinical disease features, disease duration, cognitive and physical impairment, medication, comorbidity, and sleep architecture. RESULTS: The overall frequency of RBD was 46%. According to our cohort and modified definition, there was no preferred PD subtype for RBD (p=0.142). There was no gender preference (p=0.770). RBD was associated with older age (p=0.000). Adjusted for age and gender, patients with PD and RBD had longer disease duration (p=0.024), higher Hoehn & Yahr stages (p=0.002), more falls (p=0.018), more fluctuations (p=0.005), more psychiatric comorbidity (p=0.026), and a higher dose of levodopa (p=0.002). The presence of RBD was related to slightly increased sleep efficiency (p=0.007), a higher amount of REM sleep (p=0.000), and more periodic leg movements during sleep (p=0.019). CONCLUSION: RBD is a frequent and clinically relevant nocturnal disturbance for all stages of PD. It increases with age and disease duration and may contribute to the nocturnal problems of patients with PD and their bed partners.

The role of 123I-FP-CIT-SPECT in the differential diagnosis of Parkinson and tremor syndromes: a critical assessment of 125 cases.

(123)I-FP-CIT-SPECT is useful in the differential diagnosis of Parkinson's disease (PD) and tremor syndromes. Recently, there have been reports on normal nigrostriatal uptake of radio ligands in PD patients, referred to as scans without evidence of dopaminergic deficit (SWEDDs). Furthermore, a dopaminergic deficit has been described in some cases of different tremor types. We sought to clarify the occurrence of SWEDDs in PD and a possible association of various tremor types with PD. We performed a retrospective case analysis of 125 patients with diagnostically uncertain Parkinsonian or non-Parkinsonian tremor syndromes with clinical assessments and (123)I-FP-CIT-SPECT. A total of 36/40 (90%) patients with the predominant clinical feature of a postural and/or kinetic tremor showed normal DAT SPECT; 73/85 (86%) with predominant clinical symptoms of PD showed abnormal DAT SPECT with lower overall radio ligand uptake and a significant asymmetry contralateral to the clinically more affected side. In all, 4/40 (10%) of non-Parkinsonian tremor patients had abnormal DAT SPECT, but no corresponding asymmetry of radio ligand uptake. Probable essential tremor was considered clinically in follow-up assessments although final diagnosis of these four tremor cases remains inconclusive. A total of 12/85 (14%) clinically suspected PD patients had normal DAT SPECT (SWEDDs). Clinical reassessment identified two patients with dystonic tremor. Five patients with a positive response to levodopa remained unclear. In four cases of suspected PD with normal DAT SPECT, non-neurologic diseases were identified. One case showed a complete and spontaneous remission of symptoms. DAT SPECT offers an objective method to confirm or exclude a dopaminergic deficit in tremor predominant parkinsonism for clinically inconclusive cases. There was no evidence of a decrease in DAT binding in the majority of patients with postural and/or kinetic tremor. The striatal asymmetry index is a further helpful tool for differentiating PD from non-PD tremor syndromes.

Substantia nigra echogenicity in progressive supranuclear palsy.

A normoechogenic substantia nigra (SN) is a typical finding in transcranial sonography in patients with progressive supranuclear palsy (PSP), whereas in patients with Parkinson's disease a hyperechogenic SN is characteristic. A recent classification scheme recommends the differentiation of PSP patients into those with Richardson's syndrome (RS) and those with PSP-Parkinsonism (PSP-P). We investigated 34 PSP patients (27 RS, 7 PSP-P) with ultrasound of the substantia nigra in search of differentiations in the two groups. We found that most of the PSP-P patients, according to recently published criteria, had a hyperechogenic SN (6 of 7): right (cm(2)) median 0.22, 25% percentile 0.21 and 75% percentile 0.36 (cm(2)); left (cm(2)) median 0.21, 25% percentile 0.20 and 75% percentile 0.30 and a normal third ventricle (mean mm) +/-SD: 7.1 +/- 2.43). In RS patients a normoechogenic SN (26 of 27) and an enlarged third ventricle (mean mm) +/-SD: 10.3 +/- 2.41) was found. These differences may elucidate the pathological differences of RS and PSP-P.

A randomized controlled trial of Internet-based self-help training for recurrent headache in childhood and adolescence.

Two different self-help training programs (multimodal cognitive-behavioral training (CBT) and applied relaxation (AR)) presented via the Internet were compared with an educational intervention (EDU) in an RCT. Sixty-five children and adolescents (mean age: 12.7 years) with recurrent headache (at least 2 attacks per month) were each assigned to one of the three treatment conditions. The main outcome variables related to changes in headache frequency, intensity and duration as well as the responder rate (50% reduction of headache frequency) and NNTs. Secondary outcome variables were pain catastrophizing and general well-being (depression, psychopathological symptoms and health-related quality of life). All groups showed significant reduction in headache frequency, duration and pain catastrophizing, but not in headache intensity, depression, psychopathological symptoms or health-related quality of life at post-assessment. NNTs were 2.0 for the comparison CBT and EDU; 5.2 for the comparison of AR and EDU at post-treatment. The highest responder rates at post were from CBT (63%), significantly different compared to AR (32%) and EDU (19%), whereas at follow-up no significant differences were found (CBT: 63%, AR: 56%, EDU: 55%) reflecting in the NNTs. The effects remain stable in headache frequency, pain catastrophizing and psychopathological symptoms across all groups at follow-up assessment. CBT showed the highest within-effect size in headache frequency, duration and pain catastrophizing. The results support the use of Internet programs for pediatric recurrent headache, especially given their accessibility and suitability for children and adolescents. Further studies are needed to improve their quality and efficacy.