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Functional dependency in basic activities of daily living (ADLs) is a key outcome in Parkinson's disease (PD). We aimed to define dependency in PD, using the original and MDS versions of the Unified Parkinson's Disease Rating Scale (UPDRS).We developed two algorithms to define dependency from items of UPDRS Part 2 and MDS-UPDRS Part 2 relating to basic ADLs (feeding, dressing, hygiene and walking, and getting out of a chair). We validated both algorithms using data from 1110 patients from six community-based PD incidence cohorts, testing concurrent validity, convergent validity, and predictive validity.Our optimal algorithm showed high specificity and moderate to high sensitivity versus SchwabEngland80% (specificity 95% [95% confidence interval (CI) 93-97] and sensitivity 65% [95% CI 55-73] at baseline; 88% [95% CI 85-91] and 85% [95% CI 79-97] respectively at five-years follow-up). Convergent validity was demonstrated by strong associations between dependency defined by the algorithm and cognition (MMSE), quality of life (PDQ39), and impairment (UPDRS part 3) (all p 0.001). Algorithm-defined dependency status also predicted mortality: HR for mortality in those dependent vs independent at baseline was 1.6 (95%CI 1.2-2.1) and in those dependent vs independent at five-years' follow-up was 2.2 (1.6-3.0).We have demonstrated the concurrent validity, convergent validity, and predictive validity of a UPDRS-/MDS-UPDRS-based algorithm to define functional dependency in PD. This can be used for studying dependency in any study where UPDRS or MDS-UPDRS part 2 data have been collected.

OBJECTIVE: To determine the frequency of mutations known to cause autosomal dominant Parkinson disease (PD) in a series with more than 10% of Sweden's estimated number of PD patients. METHODS: The Swedish Parkinson Disease Genetics Network was formed as a national multicenter consortium of clinical researchers who together have access to DNA from a total of 2,206 PD patients; 85.4% were from population-based studies. Samples were analyzed centrally for known pathogenic mutations in SNCA (duplications/triplications, p.Ala30Pro, p.Ala53Thr) and LRRK2 (p.Asn1437His, p.Arg1441His, p.Tyr1699Cys, p.Gly2019Ser, p.Ile2020Thr). We compared the frequency of these mutations in Swedish patients with published PD series and the gnomAD database. RESULTS: A family history of PD in first- and/or second-degree relatives was reported by 21.6% of participants. Twelve patients (0.54%) carried LRRK2 p.(Gly2019Ser) mutations, one patient (0.045%) an SNCA duplication. The frequency of LRRK2 p.(Gly2019Ser) carriers was 0.11% in a matched Swedish control cohort and a similar 0.098% in total gnomAD, but there was a marked difference between ethnicities in gnomAD, with 42-fold higher frequency among Ashkenazi Jews than all others combined. CONCLUSIONS: In relative terms, the LRRK2 p.(Gly2019Ser) variant is the most frequent mutation among Swedish or international PD patients, and in gnomAD. SNCA duplications were the second most common of the mutations examined. In absolute terms, however, these known pathogenic variants in dominant PD genes are generally very rare and can only explain a minute fraction of familial aggregation of PD. Additional genetic and environmental mechanisms may explain the frequent co-occurrence of PD in close relatives. publishedVersion

ObjectiveTo examine mortality and associated risk factors, including possible effects of mild cognitive impairment, imaging, and CSF abnormalities, in a community-based population with incident parkinsonism and Parkinson disease.MethodsOne hundred eighty-two patients with new-onset, idiopathic parkinsonism were diagnosed from January 2004 through April 2009, in a catchment area of 142,000 inhabitants in Sweden. Patients were comprehensively investigated according to a multimodal research protocol and followed prospectively for up to 13.5 years. A total of 109 patients died. Mortality rates in the general Swedish population were used to calculate standardized mortality ratio and expected survival, and Cox proportional hazard models were used to investigate independent predictors of mortality.ResultsThe standardized mortality ratio for all patients was 1.84 (95% confidence interval 1.50–2.22, p < 0.001). Patients with atypical parkinsonism (multiple system atrophy or progressive supranuclear palsy) had the highest mortality. In early Parkinson disease, a mild cognitive impairment diagnosis, freezing of gait, hyposmia, reduced dopamine transporter activity in the caudate, and elevated leukocytes in the CSF were significantly associated with shorter survival.ConclusionAlthough patients presenting with idiopathic parkinsonism have reduced survival, the survival is highly dependent on the type and characteristics of the parkinsonian disorder. Patients with Parkinson disease presenting with normal cognitive function seem to have a largely normal life expectancy. The finding of a subtle CSF leukocytosis in patients with Parkinson disease with short survival may have clinical implications.

Introduction Both polymorphisms and mutations in glucocerebrosidase ( GBA ) may influence the development of dementia in patients with Parkinson's disease. Methods Four hundred forty-two patients and 419 controls were followed for 7 years. Dementia was diagnosed using established criteria. Participants were analyzed for GBA genetic variants, including E326K, T369M, and L444P. Associations between GBA carrier status and dementia were assessed with Cox survival analysis. Results A total of 12.0% of patients with Parkinson's disease carried a GBA variant, and nearly half (22/53) of them progressed to dementia during follow-up. Carriers of deleterious GBA mutations (adjusted hazard ratio 3.81, 95% confidence interval 1.35 to 10.72; P = .011) or polymorphisms (adjusted hazard ratio 1.79; 95% confidence interval 1.07 to 3.00; P = .028) progressed to dementia more rapidly than noncarriers. Discussion GBA variants are of great clinical relevance for the development of dementia in Parkinson's disease, especially due to the relatively higher frequency of these alleles compared with other risk alleles.

BackgroundSeveral open-label studies have shown good effect of deep brain stimulation (DBS) in the caudal zona incerta (cZi) on tremor, including parkinsonian tremor, and in some cases also a benefit on akinesia and axial symptoms. The aim of this study was to evaluate objectively the effect of cZi DBS in patients with Parkinson’s disease (PD).Method25 patients with PD were randomised to either cZi DBS or best medical treatment. The primary outcomes were differences between the groups in the motor scores of the Unified Parkinson’s Disease Rating Scale (UPDRS-III) rated single-blindly at 6 months and differences in the Parkinson’s Disease Questionnaire 39 items (PDQ-39). 19 patients, 10 in the medical arm and 9 in the DBS arm, fulfilled the study.ResultsThe DBS group had 41% better UPDRS-III scores off-medication on-stimulation compared with baseline, whereas the scores of the non-surgical patients off-medication were unchanged. In the on-medication condition, there were no differences between the groups, neither at baseline nor at 6 months. Subitems of the UPDRS-III showed a robust effect of cZi DBS on tremor. The PDQ-39 domains ‘stigma’ and ‘ADL’ improved only in the DBS group. The PDQ-39 summary index improved in both groups.ConclusionThis is the first randomised blinded evaluation of cZi DBS showing its efficacy on PD symptoms. The most striking effect was on tremor; however, the doses of dopaminergic medications could not be decreased. cZi DBS in PD may be an addition to existing established targets, enabling tailoring the surgery to the needs of the individual patient.

F-18-(E)-N-(3-iodoprop-2-enyl)-2 beta-carbofluoroethoxy-3 beta-(4'-methylphenyl) nortropane (F-18-FE-PE2I) was recently developed and has shown adequate affinity and high selectivity for the dopami ...

Background: Cognitive decline and dementia are common non-motor problems in Parkinson’s disease (PD). The underlying aetiology is multifaceted and both chronic and reversible causes for cognitive decline are likely to be present. Malnutrition is frequent in the Parkinson population, both early and late in the disease, and nutritional deficiencies could play a role in some cognitive deficits. Objectives: The objective is to study the association between nutritional status with focus on iron intake and homeostasis, mild cognitive impairment (MCI), and PD dementia (PDD). Setting and Participants: This study included 73 out of 145 patients with PD participating in a population-based study in northern Sweden. Measurements: Registration of nutritional status by laboratory analyses of blood plasma and neuropsychological assessments at time of diagnosis were performed. MCI and PDD were assessed yearly up to ten years after diagnosis. Mini Nutritional Assessments (Full-MNA score) and plasma variables detecting iron homeostasis were compared between patients with MCI and patients with normal cognition (NC). Motor severity was measured using the Unified Parkinson´s disease rating scale III, (UPDRS III) and Hoehn and Yahr (H&Y) staging scale. Cox proportional Hazard model were performed to see if any variables that differed between MCI and NC could predict PDD at follow-up. Results: Patients with MCI at time of diagnosis had lower levels of plasma iron (P-Fe) and albumin (P-Albumin) as well as a lower score on Full-MNA score. Dietary intake of iron was higher in patients with MCI than in patients with NC (p = 0.012). In logistic regression models adjusted for age, sex, and UPDRS III, lower levels of P-Fe (p = 0.025) and P-Albumin (p = 0.011) and higher dietary iron intake (p = 0.019) were associated with MCI at baseline. A Cox regression model with dementia as endpoint revealed that lower levels of P-Fe increase the risk of dementia at follow-up with adjustments for age, sex, UPDRS III, and MCI at baseline (HR 95% CI = 0.87 (0.78-0.98), p = 0.021). Conclusions: Low P-Fe was associated with cognitive disturbance at baseline and predicted dementia up to ten years after diagnosis in patients with PD. Low P-Albumin and malnutrition assessed with Full-MNA score were associated with MCI at baseline but did not predict dementia at follow-up.

Dementia is a devastating manifestation of Parkinson's disease (PD). This study investigates whether a common polymorphism in the PITX3 gene (rs2281983), which is of importance for the function of dopaminergic neurons, affects the risk of developing dementia in PD and whether it affects dopamine transporter (DAT) uptake. We PITX3 genotyped 133 patients with new-onset, idiopathic PD, participating in a population-based study in Sweden. Patients were followed prospectively during 6-11years with extensive investigations, including neuropsychology and DAT-imaging with

Objectives: Cognitive decline is common in Parkinson's disease (PD), but the underlying mechanisms for this complication are incompletely understood. Genotypes affecting dopamine transmission may be of importance. This study investigates whether genotypes associated with reduced prefrontal dopaminergic tone and/or reduced dopamine D2-receptor availability (Catechol-O-methyltransferase [COMT] Val(158)Met genotype and DRD2 (CT)-T-957 genotype) affect the development of cognitive deficits in PD. Materials and methods: One hundred and 34 patients with idiopathic PD, participating in a regional, population-based study of incident parkinsonism, underwent genotyping. After extensive baseline investigations (including imaging and biomarker analyses), the patients were followed prospectively during 6-10 years with neuropsychological evaluations, covering six cognitive domains. Cognitive decline (defined as the incidence of either Parkinson's disease mild cognitive impairment [PD-MCI] or dementia [PDD], diagnosed according to published criteria and blinded to genotype) was studied as the primary outcome. Results: Both genotypes affected cognition, as shown by Cox proportional hazards models. While the COMT(158)Val/Val genotype conferred an increased risk of mild cognitive impairment in patients with normal cognition at baseline (hazard ratio: 2.13, P=.023), the DRD2(957)T/T genotype conferred an overall increased risk of PD dementia (hazard ratio: 3.22, P

ObjectiveTo determine whether neurofilament light chain protein in CSF (cNfL), a sensitive biomarker of neuroaxonal damage, reflects disease severity or can predict survival in Parkinson disease (PD).MethodsWe investigated whether disease severity, phenotype, or survival in patients with new-onset PD correlates with cNfL concentrations around the time of diagnosis in the population-based New Parkinsonism in Umeå (NYPUM) study cohort (n = 99). A second, larger new-onset PD cohort (n = 194) was used for independent validation. Association of brain pathology with the cNfL concentration was examined with striatal dopamine transporter imaging and repeated diffusion tensor imaging at baseline and 1 and 3 years.ResultsHigher cNfL in the early phase of PD was associated with greater severity of all cardinal motor symptoms except tremor in both cohorts and with shorter survival and impaired olfaction. cNfL concentrations above the median of 903 ng/L conferred an overall 5.8 times increased hazard of death during follow-up. After adjustment for age and sex, higher cNfL correlated with striatal dopamine transporter uptake deficits and lower fractional anisotropy in diffusion tensor imaging of several axonal tracts.ConclusionscNfL shows usefulness as a biomarker of disease severity and to predict survival in PD. The present results indicate that the cNfL concentration reflects the intensity of the neurodegenerative process, which could be important in future clinical trials.Classification of evidenceThis study provides Class II evidence that in patients with PD, cNfL concentrations are associated with more severe disease and shorter survival.

The influence of graphite morphology on the corrosion-fatigue mechanism in the cast compacted graphite iron SiMo1000 is investigated. Two batches of SiMo1000 with the same chemical composition but different nodularity are tested using low-cycle-fatigue tests in argon and a synthetic exhaust atmosphere at 800 °C. Decreased graphite nodularity is found to significantly reduce the corrosion resistance of SiMo1000, causing severe decarburization on the sample surface. Besides, the fatigue life is also dramatically reduced with decreased graphite nodularity. The synergy of decarburization and fatigue is found to reduce fatigue life in one of the batches.

Background: Dopamine transporter (DAT) imaging may be of diagnostic value in patients with clinically suspected parkinsonian disease. The purpose of this study was to compare the diagnostic performance of DAT imaging with positron emission computed tomography (PET), using the recently developed, highly DAT-selective radiopharmaceutical [18F]FE-PE2I (FE-PE2I), to the commercially available and frequently used method with [123I]FP-CIT (FP-CIT) single-photon emission computed tomography (SPECT) in early-stage idiopathic parkinsonian syndrome (PS). Methods: Twenty-two patients with a clinical de novo diagnosis of PS and 28 healthy controls (HC) participating in an on-going clinical trial of FE-PE2I were analyzed in this study. Within the trial protocol, participants are clinically reassessed 2 years after inclusion. A commercially available software was used for automatic calculation of FP-CIT-specific uptake ratio (SUR). MRI-based volumes of interest combined with threshold PET segmentation were used for FE-PE2I binding potential relative to non-displaceable binding (BPND) quantification and specific uptake value ratios (SUVR). Results: PET with FE-PE2I revealed significant differences between patients with a clinical de novo diagnosis of PS and healthy controls in striatal DAT availability (p

Summary Objectives We aimed to study the effect of deep brain stimulation (DBS) in the subthalamic nucleus (STN) and caudal zona incerta (cZi) on level of perceived voice tremor in patients with Parkinson disease (PD). Study Design This is a prospective nonrandomized design with consecutive patients. Methods Perceived voice tremor was assessed in patients with PD having received either STN-DBS (8 patients, 5 bilateral and 3 unilateral, aged 43.1–73.6 years; median = 61.2 years) or cZi-DBS (14 bilateral patients, aged 39.0–71.9 years; median = 56.6 years) 12 months before the assessment. Sustained vowels that were produced OFF and ON stimulation (with simultaneous l -DOPA medication) were assessed perceptually in terms of voice tremor by two raters on a four-point rating scale. The assessments were repeated five times per sample and rated in a blinded and randomized procedure. Results Three out of the 22 patients (13%) were concluded to have voice tremor OFF stimulation. Patients with PD with STN-DBS showed mild levels of perceived voice tremor OFF stimulation and a group level improvement. Patients with moderate/severe perceived voice tremor and cZi-DBS showed marked improvements, but there was no overall group effect. Six patients with cZi-DBS showed small increases in perceived voice tremor severity. Conclusions STN-DBS decreased perceived voice tremor on a group level. cZi-DBS decreased perceived voice tremor in patients with PD with moderate to severe preoperative levels of the symptom.

Objectives: The objective of this study was to examine swallowing function in patients with Parkinson's disease before and after caudal zona incerta deep brain (cZI DBS) surgery. The aims were to examine the effect of cZI DBS on swallowing safety regarding liquid and solid food, as well as to identify the effect of cZI DBS on body mass index (BMI) and specific items from part II of the Unified Parkinson's Disease Rating Scale (UPDRS). Materials and Methods: The median age of the 14 patients was 57 years (range 46–71), with a median disease duration of 6 years (range 2–13). The present sample is an extension of a previous report, into which six additional patients have been added. Fiber endoscopic examinations of swallowing function, measures of BMI, and evaluation of UPDRS part II items were made before and 12 months after surgery, with and without activated DBS. Results: There were no significant changes due to cZI DBS regarding penetration/aspiration, pharyngeal residue or premature spillage (p > .05). Median BMI increased by +1.1 kg/m2 12 months after surgery (p = .01, r = .50). All reported specific symptoms from the UPDRS part II were slight or mild. A significant improvement regarding handling of utensils was seen 12 months postoperatively (p = .03, r = −.42). Conclusions: Caudal zona incerta DBS was found not to have a negative impact on swallowing safety. A significant increase in postoperative weight was observed, and speech seemed to be slightly negatively affected, whereas handling of utensils was improved with cZI DBS. Originally published in thesis in manuscript form.

Weight loss is strongly associated with Parkinson's disease (PD) and impacts symptoms and disease progression. The aim of this study was to describe changes in body composition and to explore how body weight (BW), relates to disease progression and medication in the early phase of PD.Participants in a prospective community-based case-control study of PD were followed-up three years after initial diagnosis. Anthropometric and bioelectrical impedance spectroscopy (BIS) measurements were used together with Mini Nutritional Assessment (MNA), a 24-h recall (24-HR) and a 3-day food registration (3-DFR) to complete the evaluation of nutritional status. Disease severity was assessed using the Mini Mental State Examination (MMSE), the Unified Parkinson's Disease Rating Scale motor score (UPDRS III), and the Hoehn and Yahr rating.The PD patients' BW gained 1.62 kg (±4.60, P = 0.009), an increase that significantly correlated with fat mass (FM) (r = 0.74), waist size (r = 0.65), waist/height ratio (r = 0.64), and total skin fold (r = 0.77). Linear regression showed an association between change in BW and physical activity level (PAL) (B = -8.554; P = 0.025) confirmed by the multiple linear regression. Linear regression also revealed an association between change in FM and MMSE (B = 0.654; P = 0.027).In early PD, weight gain was revealed over three years accompanied by an increase in FM and waist circumference. An inverse relation was revealed between change in BW and PAL. The MMSE, UPDRS III, and Hoehn and Yahr rating were unchanged. Medication and swallowing difficulties were not associated with change in BW.

Dopamine transporter (DaT) imaging may be supportive in the initial clinical diagnostic workup in patients with suspected parkinsonian diseases, given that the method has the potential to detect dopaminergic degeneration. We investigated the diagnostic accuracy of visual assessment of the initial DaT single‐photon emission CT (DaT‐SPECT) with 123I‐FP‐CIT in a large group of early‐stage parkinsonian patients. After inclusion in a long‐term multidisciplinary population‐based prospective study, a baseline DaT‐SPECT was done in 171 incidental, L‐dopa‐naïve, parkinsonian patients (102 men and 69 women) and 37 healthy controls (19 men and 18 women). The results of the DaT‐SPECTs were linked to criteria‐based clinical diagnoses, which were set after a mean follow‐up of 4.6 (±1.7) years. The outcome of the visual assessment was also compared with that of a semiquantitative evaluation method using regions of interest to measure uptake ratios in the caudate and putamen. We found that visual assessment of DaT‐SPECT in clinically diagnosed incidental Parkinson's disease patients had a sensitivity of 94% and a specificity of 92%, rendering a positive likelihood ratio of 11.75 and a negative likelihood ratio of 0.07. The proportion of false positives was 1.4% and false negatives 4.8% at baseline. These figures were comparable to those of the semiquantitative method. This study demonstrates that visual interpretation of presynaptic dopamine imaging with 123I‐FP‐CIT offers reliable support in the diagnostic procedure of early parkinsonian diseases.

Parkinson's disease (PD) is a progressive, multi-focal neurodegenerative disease for which there is no effective disease modifying treatment. A critical requirement for designing successful clinical trials is the development of robust and reproducible biomarkers identifying PD in preclinical stages.To investigate the potential for a cluster of biomarkers visualized with multiple analytical platforms to provide a clinically useful tool.Gas Chromatography-Mass Spectrometry (GC-TOFMS) based metabolomics and immunoassay-based protein/peptide analyses on samples from patients with PD diagnosed in Northern Sweden. Low molecular weight compounds from both plasma and cerebrospinal fluid (CSF) from 20 healthy subjects (controls) and 20 PD patients at the time of diagnosis (baseline) were analyzed.In plasma, we found a significant increase in several amino acids and a decrease in C16-C18 saturated and unsaturated fatty acids in patients as compared to control subjects. We also observed an increase in plasma levels of pyroglutamate and 2-oxoisocaproate (ketoleucine) that may be indicative of increased metabolic stress in patients. In CSF, there was a generally lower level of metabolites in PD as compared to controls, with a specific decrease in 3-hydroxyisovaleric acid, tryptophan and creatinine. Multivariate analysis and modeling of metabolites indicates that while the PD samples can be separated from control samples, the list of detected compounds will need to be expanded in order to define a robust predictive model. CSF biomarker immunoassays of candidate peptide/protein biomarkers revealed a significant decrease in the levels of Aβ-38 and Aβ-42, and an increase in soluble APPα in CSF of patients. Furthermore, these peptides showed significant correlations to each other, and positive correlations to the CSF levels of several 5- and 6-carbon sugars. However, combining these metabolites and proteins/peptides into a single model did not significantly improve the statistical analysis.Together, this metabolomics study has detected significant alterations in plasma and CSF levels of a cluster of amino acids, fatty acids and sugars based on clinical diagnosis and levels of known protein and peptide biomarkers.

To investigate the effect of caudal zona incerta-deep brain stimulation (cZi-DBS) on word-level speech intelligibility in patients with Parkinson's disease, under both an optimal listening condition and a simulated more naturalistic listening condition.Spoken single words were extracted from read samples collected from 10 bilaterally implanted patients with PD pre- and post-cZi-DBS. Intelligibility was assessed through a transcription task performed by 32 naive listeners under two listening conditions: (i) with low-amplitude conversational speech added as background and (ii) with no added background noise. The listeners' responses were scored in terms of agreement with the intended words.Post-operatively, the total intelligibility score was significantly lower when cZi stimulation was switched on compared with off, for both listening conditions (with and without added background noise). Intelligibility was also significantly lower on stimulation compared with preoperative recordings, but only when assessed in the listening condition without background noise. The listening condition with added background noise resulted in significantly lower intelligibility scores compared with the no added noise condition for all stimulation conditions.The results of this study indicate that cZi-DBS in patients with PD can be detrimental to word-level speech intelligibility.

Objective: The need for age-adjusted and/or sex-adjusted reference values in dopamine transporter (DAT) and dopamine D2 receptor (D2R) imaging with single-photon emission computed tomography (SPECT ...

Objectives: The management of Parkinson’s disease (PD) has been improved, but management of signs like swallowing problems is still challenging. Deep brain stimulation (DBS) alleviates the cardinal motor symptoms and improves quality of life, but its effect on swallowing is not fully explored. The purpose of this study was to examine self-reported swallowing-specific quality of life before and after caudal zona incerta DBS (cZI DBS) in comparison with a control group. Methods: Nine PD patients (2 women and 7 men) completed the self-report Swallowing Quality of Life questionnaire (SWAL-QOL) before and 12 months after cZI DBS surgery. The postoperative data were compared to 9 controls. Median ages were 53 years (range, 40-70 years) for patients and 54 years (range, 42-72 years) for controls. Results: No significant differences were found between the pre- or postoperative scores. The SWAL-QOL total scores did not differ significantly between PD patients and controls. The PD patients reported significantly lower scores in the burden subscale and the symptom scale. Conclusions: Patients with PD selected for cZI DBS showed good self-reported swallowing-specific quality of life, in many aspects equal to controls. The cZI DBS did not negatively affect swallowing-specific quality of life in this study.

Objective:To determine if blood neurofilament light chain (NfL) protein can discriminate between Parkinson disease (PD) and atypical parkinsonian disorders (APD) with equally high diagnostic accuracy as CSF NfL, and can therefore improve the diagnostic workup of parkinsonian disorders.Methods:The study included 3 independent prospective cohorts: the Lund (n = 278) and London (n = 117) cohorts, comprising healthy controls and patients with PD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), as well as an early disease cohort (n = 109) of patients with PD, PSP, MSA, or CBS with disease duration ≤3 years. Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method, and the diagnostic accuracy to distinguish PD from APD was investigated.Results:We found strong correlations between blood and CSF concentrations of NfL (ρ ≥ 0.73–0.84, p ≤ 0.001). Blood NfL was increased in patients with MSA, PSP, and CBS (i.e., all APD groups) when compared to patients with PD as well as healthy controls in all cohorts (p < 0.001). Furthermore, in the Lund cohort, blood NfL could accurately distinguish PD from APD (area under the curve [AUC] 0.91) with similar results in both the London cohort (AUC 0.85) and the early disease cohort (AUC 0.81).Conclusions:Quantification of blood NfL concentration can be used to distinguish PD from APD. Blood-based NfL might consequently be included in the diagnostic workup of patients with parkinsonian symptoms in both primary care and specialized clinics.Classification of evidence:This study provides Class III evidence that blood NfL levels discriminate between PD and APD.

Purpose The purpose of the present study was to examine the effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the caudal zona incerta (cZi) pitch characteristics of connected speech in patients with Parkinson’s disease (PD). Method The authors evaluated 16 patients preoperatively and 12 months after DBS surgery. Eight patients were implanted in the STN (ages 51–72 years; M = 63 years). Six received bilateral implantation and 2 unilateral (left) implantation. Eight patients were bilaterally implanted in the cZi (ages 49–71 years; M = 60.8 years). Preoperative assessments were made after a levodopa challenge (approximately 1.5 times the ordinary dose). All postoperative examinations were made off and on stimulation with a clinically optimized dose of levodopa. Measurements of pitch range and variability were obtained from each utterance in a recorded read speech passage. Results Pitch range and coefficient of variation showed an increase in patients under STN–DBS. Patients under cZi–DBS showed no significant effects of treatment on investigated pitch properties. Conclusion STN–DBS was shown to increase pitch variation and range. The results provided no evidence of cZi–DBS having a beneficial effect on PD patients' pitch variability.

Introduction Flight-induced neck pain is common in high performance jet pilots, with incidents frequently attributed to high Gz flight maneuvers. The additional load of helmet-mounted night vision goggles (NVG) is believed to increase the risk, possibly from neck muscle strain in counteracting muscles. Hence, the aim was to investigate the effect of NVG on neck muscle strain as well as on the activity level distribution through a simulated flight session in air force pilots. Methods In this post hoc randomized crossover trial, four senior air force pilots each completed two identical 1.5-h dynamic flight simulations in a human centrifuge: one with a standard helmet and NVG, and one with a standard helmet only. Simulations included repeated exposure to 3-7 Gz, during which neck muscle activity was recorded bilaterally from the anterior neck, the upper and lower posterior neck, and the upper shoulders. The number of muscle activities surpassing 50% of maximum voluntary electrical activity (MVE) and total time of activity at each MVE percentile were compared between NVG and control flights. Results There was no overall effect in number of neck strain activities between NVG and control flights; however, significantly more activities emerged in the anterior neck. In addition, MVE percentile data showed a tendency of higher activity in the lower posterior neck during NVG flights. Conclusions The results showed that the additional load of helmet-mounted NVG increases neck muscle strain in anterior stabilizing muscles, indicating that the inertia of head-worn NVG elevates the risk of flight-related neck pain. Pousette MW, Lo Martire R, Linder J, Kristoffersson M, Ang BO. Neck muscle strain in air force pilots wearing night vision goggles. Aerosp Med Hum Perform. 2016; 87(11):928-932.

A Scandinavian multi-centre study replicates 11 susceptibility loci from genome-wide association studies in Parkinson's disease

Objective The purpose of the present study was to examine if there was a negative effect of caudal Zona Incerta deep brain stimulation (cZI DBS) on pharyngeal swallowing function in Parkinson’s patients (PD). There are no former reports on swallowing and cZI DBS. Methods Eight patients (aged 49 to 71 years; median 62) were evaluated pre- and postoperatively, at six and 12 months after DBS surgery. Evaluation tools were Fiberoptic Endoscopic Evaluation of Swallowing examinations and patients’ self-assessments of the swallowing function including a visual analogue scale and quality of life related questions. The swallowing protocol included Rosenbeck’s Penetration-Aspiration Scale, Secretion Severity Scale and parameters for pre-swallow spillage, pharyngeal residue and pharyngeal clearance. Results There was no clear-cut effect of neurostimulation postoperatively at six and 12 months on any of the swallowing parameters except for pre-swallow spillage which was slightly worsened in the stimulation on condition 12m postoperatively. The answers to the self assessment questions did not vary significantly. Conclusions The effect of the stimulation on swallowing function varied among individuals but the overall outcome was that cZI DBS did not seem to have a negative influence on swallowing function in the eight patients studied.

The current "gold-standard" for Parkinson's disease (PD) diagnosis is based primarily on subjective clinical rating scales related with motor features. Molecular biomarkers that are objective and quantifiable remain attractive as clinical tools to detect PD prior to its motor onsets.Here, we aimed to identify, develop, and validate plasma-based circulating microRNA (miRNAs) as biomarkers for PD.Global miRNA expressions were acquired from a discovery set of 32 PD/32 controls using microarrays. k-Top Scoring Pairs (k-TSP) algorithm and significance analysis of microarrays (SAM) were applied to obtain comprehensive panels of PD-predictive biomarkers. TaqMan miRNA-specific real-time PCR assays were performed to validate the microarray data and to evaluate the biomarker performance using a new replication set of 42 PD/30 controls. Data was analyzed in a paired PD-control fashion. The validation set was composed of 30 PD, 5 progressive supranuclear palsy, and 4 multiple system atrophy samples from a new clinical site.We identified 9 pairs of PD-predictive classifiers using k-TSP analysis and 13 most differentially-expressed miRNAs by SAM. A combination of both data sets produced a panel of PD-predictive biomarkers: k-TSP1 (miR-1826/miR-450b-3p), miR-626, and miR-505, and achieved the highest predictive power of 91% sensitivity, 100% specificity, 100% positive predicted value, and 88% negative predicted value in the replication set. However, low predictive values were shown in the validation set.This proof-of-concept study demonstrates the feasibility of using plasma-based circulating miRNAs as biomarkers for neurodegenerative disorders such as PD and shows the challenges of molecular biomarker research using samples from multiple clinical sites.

The differential diagnosis of idiopathic parkinsonism can be very challenging, especially early in the course of the disease. Oculomotor function has been reported to differ between the diseases constituting idiopathic parkinsonism. A detailed examination of the oculomotor functions could thus possibly be useful in the early differential diagnostic procedure. Oculomotor function could also differ between subgroups of patients with Parkinson's disease (PD). We examined the oculomotor function in a population-based incidence cohort with newly diagnosed idiopathic parkinsonism and 38 controls. We examined 135 patients with parkinsonism 105 PD, 11 progressive supranuclear palsy (PSP), and 19 multiple system atrophy with predominant parkinsonism (MSA-P)] within 3 months of their first visit to our clinic and before initiation of dopaminergic medication. The oculomotor measurements were repeated after 12 months. The clinical diagnosis was that of the latest clinical follow-up (median follow-up was 3 years). All patients were examined with (123)I-N-(omega)-fluoropropyl-2-β-carbomethoxy-3-β-(4-iodophenyl) nortropane single-photon emission computed tomography (FP-CIT SPECT), and only patients with pathological uptake of the ligand were included. Pathological changes in the oculomotor function were found in all patient groups compared to controls at the baseline examination. In PD, there were correlations between total axial motor scores and vertical saccade velocity and precision, horizontal saccade velocity and precision, and smooth pursuit gain at 20 and 30°/s. Oculomotor test results could not separate the different forms of idiopathic parkinsonism in the early phase from each other. Few changes in the oculomotor functions were observed between the baseline and the 12-month follow-up examinations. No correlations were found between the oculomotor measurements and disease severity or duration.

OBJECTIVE: To evaluate energy and nutrient intake in newly diagnosed Parkinson's disease (PD) patients and association between olfaction and nutrient density of the diet. DESIGN: Baseline data from a prospective cohort study. SUBJECTS: Eighty-seven patients and 28 age- and sex-matched controls participated in the study. METHODS: Dietary intake was assessed by using 3-day dietary records and 24-hour dietary recalls. The Brief Smell Identification Test (B-SIT) was used to test olfaction. RESULTS: Patients, compared with controls, had lower intake of polyunsaturated fatty acids (P = 0.024) and a higher intake of carbohydrates (P = 0.027) in energy percent (E%). Lower intake of protein (E%) (P = 0.045), and a low nutrient density of folate (P = 0.022), magnesium (P = 0.012), and phosphorus (P = 0.029) were associated with lower B-SIT score in both patients and controls. PD patients had a lower B-SIT score than controls (P < 0.001). CONCLUSION: The results indicate a higher relative contribution of energy from carbohydrates in PD patients. An association between low protein, folate, magnesium, and phosphorus density of the diet and olfaction was seen in the whole population.

Objective: To evaluate the reproducibility of quantitative sensory testing (QST), performed with the method-of-limits (MLI) at different test intervals, by assessing the inter- and intra-individual variation of thermal cold (CT) and warm (WT) perception thresholds, and of thermal cold- (CPT) and heat pain (HPT) thresholds. Methods: QST with the MLI was performed in 38 healthy subjects in three repeated and pseudo-randomized test sessions, done at three occasions (days 1, 2 and 7). Results: At repeated testing, none of the thermal threshold estimates showed systematic significant differences, neither between days nor between sessions within the same day, when determined as first tests (FT), and for CT and WT also after thermal pain assessment (aTPA). However, when determined directly aTPA, both CT and WT were noted significantly higher. Also the coefficients of variation and repeatability showed increased values aTPA. Conclusions: The high reproducibility show that the MLI is a feasible method for thermal QST, with reproducible results both at shorter and longer test intervals, on condition that temperature thresholds are determined before any painful thermal stimuli are given, as the latter influence both CT and WT assessments. Significance: The findings show that QST with the MLI is a reliable tool for indirect evaluation of human small nerve fiber function.

The differential diagnosis of parkinsonian disorders is difficult, especially early in the course of the diseases. The clinical subtypes of Parkinson's disease (PD) have not so far been described in newly diagnosed patients. We present a prospective incidence cohort study of patients with idiopathic parkinsonian syndromes in the Umea region in northern Sweden identified over a 4-year period. The clinical diagnoses were re-evaluated at follow-up visits at 12 months. We found 138 patients with parkinsonism: 112 PD, 12 multiple system atrophy with predominant parkinsonism (MSA-P), six progressive supranuclear palsy (PSP) and eight unclassifiable patients. The crude incidences for all age ranges per 100,000 were: PD 19.7 (95% confidence interval 16.1-23.3); MSA-P 2.1 (1.1-3.7); PSP 1.1 (0.4-2.4); idiopathic parkinsonism 24.3 (20.2-28.4). Age-standardized to the average Swedish population 2004-2007: PD 22.5 (18.3-26.7); MSA-P 2.4 (1.2-4.2); PSP 1.2 (0.4-2.6); idiopathic parkinsonism 27.5 (22.9-32.1). The crude annual incidence rate for PD, with exclusion of patients with normal dopamine receptor uptake (FP-CIT-SPECT), was 18.8 per 100,000 (95% confidence interval 15.2-22.4), age-adjusted to the average Swedish population 2004 to 2007: 21.5 (17.4-25.6). The incidence rates did not differ significantly between men and women. The cumulative incidence of PD up to 89 years of age was for men 3.4%, for women 2.6%, and for both sexes combined 2.9%. The annual incidence rates found for PD, idiopathic parkinsonism, MSA-P and PSP are among the highest reported.

BACKGROUND AND PURPOSE: The study aims to describe the frequency, pattern and determinants of cognitive function in patients with newly diagnosed Parkinson's disease (PD); to compare patients with ...

Using hybrid-blocked/event-related fMRI and the 2-back task we aimed to decompose tonic and phasic temporal dynamics of basal ganglia response abnormalities in working memory associated with early untreated Parkinson's disease. In view of the tonic/phasic dopamine hypothesis, which posits a functional division between phasic D(2)-dependent striatal updating processes and tonic D(1)-dependent prefrontal context-maintenance processes, we predicted that newly diagnosed, drug-naïve Parkinson's disease patients, with selective striatal dopamine deprivation, would demonstrate transient rather than sustained activation changes in the basal ganglia during 2-back performance. Task-related activation patterns within discrete basal ganglia structures were directly compared between patients and healthy elderly controls. The obtained results yielded uniquely transient underactivation foci in caudate nuclei, putamen and globus pallidus in Parkinson's disease patients, which indicates suboptimal phasic implementation of striatal D(2)-dependent gating mechanisms during updating. Sustained underactivation was only seen in the anterior putamen, which may reflect initial signs of tonic control impairment. No significant changes were exhibited in prefrontal cortex. The present findings resonate well with the tonic/phasic dopamine account and suggest that basal ganglia under-recruitment associated with executive dysfunction in early Parkinson's disease might predominantly stem from deficiencies in phasic executive components subserved by striatum.

The influence of mechanical strength for aluminium castings is often correlated in the literature to the occurrence of cast defects like porosity. However, because aluminium castings in the automot ...

The caudal zona incerta (cZI) is a promising, clinically beneficial target for deep brain stimulation (DBS) in Parkinson's disease (PD). To assess whether DBS of the cZI affects the rate of dopamine terminal dysfunction, PD patients with and without DBS were followed prospectively with I FP-Cit single photon emission tomography from the first diagnosis and up to 8 years.Six patients underwent DBS of the cZI during the survey period. Twenty-two PD patients only on pharmacotherapy served as controls. I FP-Cit and clinical assessment were performed at baseline and after 1, 3 and 5 years in all patients. Ten patients also underwent a I FP-Cit after 8 years. Image data were evaluated semiquantitatively. Mixed-model analysis was used to assess the relative change in I FP-Cit uptake and comparison between surgically and conservatively treated PD patients.The relative decrease in I FP-Cit uptake was more pronounced in DBS-treated patients than in controls in the more affected caudate (P=0.037) and putamen (P=0.013). The annual decrease rates were higher in the less affected than the more affected putamen, and were slightly greater in DBS-treated patients (4.8%, 95%confidence interval: 8.5-2.2%) than in controls (4.0%, 95% confidence interval: 5.1-3.1%).This long-term prospective study confirms that the underlying dopaminergic dysfunction continues despite clinical improvement in PD patients with DBS of the cZI. A slightly faster rate of decrease in I FP-Cit uptake in these patients compared with conservatively treated PD patients may reflect a more aggressive form of PD.

The causes of Parkinson's disease (PD) are unknown in the majority of patients. The GCH1 gene encodes GTP-cyclohydrolase I, an important enzyme in dopamine synthesis. Co-occurrence of dopa-responsive dystonia (DRD) and a PD phenotype has been reported in families with GCH1 mutations. Recently, rare coding variants in GCH1 were found to be enriched in PD patients, indicating a role for the enzyme in the neurodegenerative process.To further elucidate the contribution of GCH1 mutations to sporadic PD, we examined its coding exons in a targeted deep sequencing study of 509 PD patients (mean age at onset 56.7 ± 12.0 years) and 230 controls. We further included the tyrosine hydroxylase gene TH, also known to cause DRD. Gene dose assessments were performed to screen for large copy number variants in a subset of 48 patients with early-onset PD.No putatively pathogenic GCH1 mutations were found. The frequency of rare heterozygous variants in the TH gene was 0.69% (7/1018) in the patient group and 0.22% (1/460) in the control group (p = 0.45).Previous studies have found that coding variants in the GCH1 gene may be considered a risk factor for PD. Our study indicates that mutations in GCH1 are rare in late-onset PD. Several patients carried heterozygous variants in the TH gene that may affect protein function. Our study was not designed to determine with certainty if any of these variants play a role as risk factors for late-onset PD.

The automotive industry always strives to achieve light weight components to reduce fuel consumption and to meet environmental requirements. One way to obtain weight reduction is to replace steel c ...

Aluminium is a lightweight material with high strength and good corrosion resistance among other beneficial properties. Thanks to these properties, aluminium is more extensively used in the vehicle ...

Mechanical load and EMG activity in the neck induced by different head-worn equipment and neck postures

Many individuals with Parkinson's disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (β-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency A(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125G>A (p.(G709S))) shifted the Aβ spectrum from Aβ40 to Aβ39 and Aβ37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD.

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ 42 ) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10 −25 ). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau ( P = .0110) but not Aβ 42 suggesting that TREM2 's role in AD may involve tau dysfunction.

The PARK16 locus, spanning five genes on chromosome 1, was among the first genetic regions to show genome-wide association in Parkinson's disease (PD). Subsequent investigations have found variability in PARK16 top-hits and association patterns across populations, and the implicated genes and mechanisms are currently unclear. In the present study, we aimed to explore the contribution of PARK16 variability to PD risk in a Scandinavian population. We genotyped 17 single-nucleotide polymorphisms in a case-control sample set of 2570 individuals from Norway and Sweden to fine map the locus. Targeted resequencing of the full coding regions of SLC45A3, NUCKS1, RAB7L1, SLC41A1 and PM20D1 was performed in DNA pools from a subset of 387 patient samples. We find evidence for an association with PD for rs1775143 as well as a haplotype located around the 5' region of RAB7L1, implicating variants which are not in high linkage disequilibrium with the strongest signal from a recent large meta-analysis in Caucasians. We also provide suggestive support for epistasis between RAB7L1 and LRRK2 as previously hypothesized by others. Comparing our results with previous work, allelic heterogeneity at PARK16 appears likely, and further studies are warranted to disentangle the complex patterns of association and pinpoint the functionally relevant variants.

Ear advantage during a dichotic listening task tends to mirror speech lateralization. Previous studies in stroke patients have shown that lesions in the dominant hemisphere often seem to produce changes in ear advantage. In this study six Parkinson's disease (PD) patients treated for motor symptoms with deep brain stimulation (DBS) of the left subthalamic nucleus (STN) were tested preoperatively and at approximately 6 and 18 months postoperatively with a dichotic listening task. Results show a significant decline of the right ear advantage over time. In three of the patients a right ear advantage preoperatively changed to a left ear advantage 18 months postoperatively. This suggests the possibility that additional longitudinal studies of this phenomenon could serve as a model for understanding changes in indirect measures of speech lateralization in stroke patients.

Purpose The present study aimed at comparing the effects of deep brain stimulation (DBS) treatment of the subthalamic nucleus (STN) and the caudal zona incerta (cZi) on the proficiency in achieving oral closure and release during plosive production of people with Parkinson's disease. Method Nineteen patients participated preoperatively and 12 months after DBS surgery. Nine patients had implantations in the STN, 7 bilaterally and 2 unilaterally (left). Ten had bilateral implantations in the cZi. Postoperative examinations were made off and on stimulation. All patients received simultaneous L-dopa treatment in all conditions. For a series of plosives extracted from a reading passage, absolute and relative measures of duration of frication and amplitude of plosive release were compared between conditions within each treatment group. Results Relative duration of frication increased in voiceless plosives in the on-stimulation condition in cZi patients. Similar trends were observed across the data set. Duration of prerelease frication and the release peak prominence increased in voiceless plosives on stimulation for both groups. Conclusion The increased release prominence suggests that patients achieved a stronger closure gesture because of DBS but that the increased energy available resulted in increased frication.

The present study investigates the influence of laser cutting as compared to conventional mechanical cutting on the fatigue properties of steel sheet. 6 grades of steel sheet were included in the study; 1 deep drawing steel, 2 high strength steels of which 1 dual phase steel, 2 variants of austenitic and 1 of duplex stainless steels. Specimens manufactured through mechanical and laser cutting were fatigue tested both at constant stress amplitudes and at variable stress amplitudes using a truncated Gaussean spectrum. Defect distributions on the cut edges were measured quantitatively. The fatigue tests showed that the fatigue strength was higher after laser cutting than after mechanical cutting. The relative difference was larger for the higher strength steels than for the lower strength steels. A model to predict the fatigue strength was developed using defect distribution measurements on the cut edges combined with linear elastic fracture mechanics. The model could in a reasonable way describe the differences in fatigue strengths of specimens manufactured with the different cutting processes.