Motor Efficacy of Subcutaneous DIZ102, Intravenous DIZ101 or Intestinal Levodopa/Carbidopa Infusion.

BACKGROUND: It has been suggested that carbidopa at high blood concentrations may counter the therapeutic effect of levodopa in Parkinson's disease by entering the brain and blocking central levodopa conversion to dopamine. We previously demonstrated equivalent plasma levodopa concentration in patients with Parkinson's disease during 16 h of (1) intravenous carbidopa/levodopa (DIZ101) infusion, (2) subcutaneous carbidopa/levodopa (DIZ102) infusion or (3) intestinal carbidopa/levodopa gel infusion. Plasma levels of carbidopa were however approximately four times higher with DIZ101 and DIZ102 than with LCIG, and higher than those usually observed with oral levodopa/carbidopa. OBJECTIVES: To investigate if high carbidopa blood concentrations obtained with parenteral levodopa/carbidopa (ratio 8:1) counter the effect of levodopa on motor symptoms. METHODS: Eighteen patients with advanced Parkinson's disease were administered DIZ101, DIZ102, and intestinal levodopa/carbidopa gel for 16 h on different days in randomized order. Video recordings of a subset of the motor examination in the Unified Parkinson's Disease Rating Scale (UPDRS) were evaluated by raters blinded for treatment and time. Motor function was also measured using a wrist-worn device monitoring bradykinesia, dyskinesia, and tremor (Parkinson KinetiGraph). RESULTS: There was no tendency for poorer levodopa effect with DIZ101 or DIZ102 as compared to LCIG. CONCLUSION: Although DIZ101 or DIZ102 causes approximately four times higher plasma carbidopa levels than LCIG, patients responded equally well to all treatments. The results do not indicate that high plasma carbidopa levels hamper the motor efficacy of levodopa.

"I'm still the person I am. Not the body it has become." An active but challenging life with cervical dystonia.

BACKGROUND: Improvement of activity and participation for the disabled and chronically ill is an important aim of rehabilitation. Cervical dystonia is a neurological movement disorder characterized by involuntary contractions of the neck muscles. Until now, research has identified factors contributing to disability rather than factors which may make it easier to be active and participate in the community. OBJECTIVE: Explore and describe perceived experiences of activity and participation in daily life as experienced by persons with cervical dystonia. METHODS: Sixteen informants participated in this semi-structured interview study. Inductive qualitative content analysis was performed to understand and interpret experiences shared by the informants. RESULTS: Results from the analysis generated two themes "An active life" and "A challenging life" and six sub-themes: Using helpful coping strategies, Accepting a new life situation, Adhering to BT treatment, Facing the negative impact of stress, Experiencing a negative self-image and Suffering from pain and fatigue. CONCLUSIONS: Our results support the importance of actions using a rehabilitation approach that consider both motor and non-motor symptoms. Future studies should compare the effects of physiotherapy taking into account wishes and challenges in patients' everyday life versus traditional physiotherapy addressing mostly the motor disorder.

Quantitative brain stem assessment in discriminating neurodegenerative disorders from normal pressure hydrocephalus.

BACKGROUND AND PURPOSE: Differentiating idiopathic normal pressure hydrocephalus (iNPH) from neurodegenerative disorders such as progressive supranuclear palsy (PSP), Multiple System Atrophy-parkinsonian type (MSA-P), and vascular dementia (VaD) is challenging due to overlapping clinical and neuroimaging findings. This study assesses if quantitative brain stem and cerebellum metrics can aid in this differentiation. METHODS: We retrospectively compared the sagittal midbrain area, midbrain to pons ratio, MR parkinsonism index (MRPI), and cerebellar atrophy in 30 PSP patients, 31 iNPH patients, 27 MSA-P patients, 32 VaD patients, and 25 healthy controls. Statistical analyses determined group differences, sensitivity, specificity, and the area under the receiver operating characteristic curves. RESULTS: There was an overlap in midbrain morphology between PSP and iNPH, as assessed with MRPI, midbrain to pons ratio, and midbrain area. A cutoff value of MRPI > 13 exhibited 84% specificity in distinguishing PSP from iNPH and 100% in discriminating PSP from all other conditions. A cutoff value of midbrain to pons ratio at <0.15 yielded 95% specificity for differentiating PSP from iNPH and 100% from all other conditions. A cutoff value of midbrain area at <87 mm2 exhibited 97% specificity for differentiating PSP from iNPH and 100% from all other conditions. All measures showed low sensitivity. Cerebellar atrophy did not differ significantly among groups. CONCLUSION: Our study questions MRPI's diagnostic performance in distinguishing PSP from iNPH. Simpler indices such as midbrain to pons ratio and midbrain area showed similar or better accuracy. However, all these indices displayed low sensitivity despite significant differences among PSP, MSA-P, and VaD.

Comparison of quantitative [11C]PE2I brain PET studies between an integrated PET/MR and a stand-alone PET system.

PET/MR systems demanded great efforts for accurate attenuation correction (AC) but differences in technology, geometry and hardware attenuation may also affect quantitative results. Dedicated PET systems using transmission-based AC are regarded as the gold standard for quantitative brain PET. The study aim was to investigate the agreement between quantitative PET outcomes from a PET/MR scanner against a stand-alone PET system. Nine patients with Parkinsonism underwent two 80-min dynamic PET scans with the dopamine transporter ligand [11C]PE2I. Images were reconstructed with resolution-matched settings using 68Ge-transmission (stand-alone PET), and zero-echo-time MR (PET/MR) scans for AC. Non-displaceable binding potential (BPND) and relative delivery (R1) were evaluated using volumes of interest and voxel-wise analysis. Correlations between systems were high (r ≥ 0.85) for both quantitative outcome parameters in all brain regions. Striatal BPND was significantly lower on PET/MR than on stand-alone PET (-7%). R1 was significantly overestimated in posterior cortical regions (9%) and underestimated in striatal (-9%) and limbic areas (-6%). The voxel-wise evaluation revealed that the MR-safe headphones caused a negative bias in both parametric BPND and R1 images. Additionally, a significant positive bias of R1 was found in the auditory cortex, most likely due to the acoustic background noise during MR imaging. The relative bias of the quantitative [11C]PE2I PET data acquired from a SIGNA PET/MR system was in the same order as the expected test-retest reproducibility of [11C]PE2I BPND and R1, compared to a stand-alone ECAT PET scanner. MR headphones and background noise are potential sources of error in functional PET/MR studies.

Pain in patients with motor neuron disease: Variation of pain and association with disease severity, health-related quality of life and depression - A longitudinal study.

OBJECTIVES: To describe levels of pain over time during disease progression in individual patients and for a total sample of patients with motor neuron disease (MND), respectively, and to examine associations between pain, disease severity, health-related quality of life (HRQOL), and depression. METHODS: A prospective cohort study was conducted on 68 patients with MND, including data collected on five occasions over a period of 2 years. Pain was assessed using the Brief Pain Inventory - Short Form. Depression was assessed using the Amyotrophic Lateral Sclerosis (ALS)-Depression-Inventory (ADI-12). Disability progression was measured using the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Version (ALSFRS-R). HRQOL was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5). RESULTS: Participants reported great individual variation over time. The median level of pain was 4 (min 0 and max 10). Higher levels of pain during the last 24 h were associated with higher depression scores (ADI-12), poorer quality of life (ALSAQ-5), and lower reporting of fine and gross motor skills (ALSFRS-R). Baseline pain levels did not predict future values of depression and function. Individuals reporting average pain >3 experienced more hopelessness toward the future and reported higher depression scores compared with participants reporting average pain <3. SIGNIFICANCE OF RESULTS: Great within-individual variation of pain intensity was reported. Pain intensity was associated with depression, function and HRQOL cross-sectionally, but it did not have a strong prognostic value for future depression, function, or HRQOL. Patients with MND should be offered frequent assessment of pain and depressive symptoms in person-centered care, allowing for individualization of treatment.

Patients accept therapy using embryonic stem cells for Parkinson's disease: a discrete choice experiment.

BACKGROUND: New disease-modifying ways to treat Parkinson's disease (PD) may soon become a reality with intracerebral transplantation of cell products produced from human embryonic stem cells (hESCs). The aim of this study was to assess what factors influence preferences of patients with PD regarding stem-cell based therapies to treat PD in the future. METHODS: Patients with PD were invited to complete a web-based discrete choice experiment to assess the importance of the following attributes: (i) type of treatment, (ii) aim of treatment, (iii) available knowledge of the different types of treatments, (iv) effect on symptoms, and (v) risk for severe side effects. Latent class conditional logistic regression models were used to determine preference estimates and heterogeneity in respondents' preferences. RESULTS: A substantial difference in respondents' preferences was observed in three latent preference patterns (classes). "Effect on symptoms" was the most important attribute in class 1, closely followed by "type of treatment," with medications as preferred to other treatment alternatives. Effect on symptoms was also the most important attribute in class 2, with treatment with hESCs preferred over other treatment alternatives. Likewise for class 3, that mainly focused on "type of treatment" in the decision-making. Respondents' class membership was influenced by their experience in treatment, side effects, and advanced treatment therapy as well as religious beliefs. CONCLUSIONS: Most of the respondents would accept a treatment with products emanating from hESCs, regardless of views on the moral status of embryos. Preferences of patients with PD may provide guidance in clinical decision-making regarding treatments deriving from stem cells.

Levels of inflammatory cytokines MCP-1, CCL4, and PD-L1 in CSF differentiate idiopathic normal pressure hydrocephalus from neurodegenerative diseases.

BACKGROUND: Neuroinflammatory processes have been suggested to play a role in the pathophysiology of neurodegenerative diseases and post-hemorrhagic hydrocephalus, but have rarely been investigated in patients with idiopathic normal pressure hydrocephalus (iNPH). The aim of this study was to investigate whether levels of inflammatory proteins in CSF are different in iNPH compared to healthy controls and patients with selected neurodegenerative disorders, and whether any of these markers can aid in the differential diagnosis of iNPH. METHODS: Lumbar CSF was collected from 172 patients from a single center and represented iNPH (n = 74), Alzheimer's disease (AD) (n = 21), mild cognitive impairment (MCI) due to AD (n = 21), stable MCI (n = 22), frontotemporal dementia (n = 13), and healthy controls (HC) (n = 21). Levels of 92 inflammatory proteins were analyzed using a proximity extension assay. As a first step, differences between iNPH and HC were investigated, and proteins that differed between iNPH and HC were then compared with those from the other groups. The linear regressions were adjusted for age, sex, and plate number. RESULTS: Three proteins showed higher (MCP-1, p = 0.0013; CCL4, p = 0.0008; CCL11, p = 0.0022) and one lower (PD-L1, p = 0.0051) levels in patients with iNPH compared to HC. MCP-1 was then found to be higher in iNPH than in all other groups. CCL4 was higher in iNPH than in all other groups, except in MCI due to AD. PD-L1 was lower in iNPH compared to all other groups, except in stable MCI. Levels of CCL11 did not differ between iNPH and the differential diagnoses. In a model based on the four proteins mentioned above, the mean area under the receiver operating characteristic curve used to discriminate between iNPH and the other disorders was 0.91. CONCLUSIONS: The inflammatory cytokines MCP-1 and CCL4 are present at higher-and PD-L1 at lower-levels in iNPH than in the other investigated diagnoses. These three selected cytokines may have diagnostic potential in the work-up of patients with iNPH.

Phosphorylated α-synuclein in skin Schwann cells: a new biomarker for multiple system atrophy.

Multiple system atrophy (MSA) is characterized by accumulation of phosphorylated α-synuclein (p-syn) as glial cytoplasmic inclusions in the brain and a specific biomarker for this disorder is urgently needed. We aimed at investigating if p-syn can also be detected in skin Remak non-myelinating Schwann cells (RSCs) as Schwann cell cytoplasmic inclusions (SCCi) and may represent a reliable clinical biomarker for MSA. This cross-sectional diagnostic study evaluated skin p-syn in 96 patients: 46 with probable MSA (29 with parkinsonism type MSA and 17 with cerebellar type MSA), 34 with Parkinson's disease (PD) and 16 with dementia with Lewy bodies (DLB). We also included 50 healthy control subjects. Patients were recruited from five different medical centres. P-syn aggregates in skin sections were stained by immunofluorescence, followed by analyses with confocal microscopy and immuno-electron microscopy. All analyses were performed in a blinded fashion. Overall, p-syn aggregates were found in 78% of MSA patients and 100% of patients with PD/DLB, whereas they could not be detected in controls. As for neuronal aggregates 78% of MSA patients were positive for p-syn in somatic neurons, whereas all PD/DLB patients were positive in autonomic neurons. When analysing the presence of p-syn in RSCs, 74% of MSA patients were positive, whereas no such SCCi could be observed in PD/DLB patients. Analyses by immuno-electron microscopy confirmed that SCCi were only found in cases with MSA and thus absent in those with PD/DLB. In conclusion, our findings demonstrate that (i) fibrillar p-syn in RSCs is a pathological hallmark of MSA and may be used as a specific and sensitive disease biomarker; (ii) in Lewy body synucleinopathies (PD/DLB) only neurons contain p-syn deposits; and (iii) the cell-specific deposition of p-syn in the skin thus mirrors that of the brain in many aspects and suggests that non-myelinated glial cells are also involved in the MSA pathogenesis.

Attitudes and values among the Swedish general public to using human embryonic stem cells for medical treatment.

BACKGROUND: The use of human embryonic stem cells (ES cells) for the development of medical therapies is surrounded with moral concerns. The aim of this study was to assess the public's attitudes toward the use of ES cells for treatment of Parkinson's disease (PD) and other diseases, what factors are most important to consider when using ES cells for drug development, and if there is an association between religious beliefs and attitudes toward using ES cells for medical treatment. METHODS: A randomly selected sample of the Swedish public, aged 18-87-years-old, completed an online survey (n = 467). The survey assessed socio-demographics, religious views, perceived moral status of the embryo, and attitudes toward using ES cells for medical treatment of PD and other diseases. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) for positive vs. negative attitude toward using ES cells for drug development were computed using logistic regression. RESULTS: The respondents were positive about using ES for treatment; specifically, 70% totally agreed that it is acceptable to use ES cells for treatment of PD, while 40% totally agreed that it is acceptable to use ES cells for treatment but induced pluripotent cells is just as efficient. Religion being of little importance in one's life was associated with a positive attitude toward using ES cells for treatment of PD (adjusted OR 6.39, 95% CI 2.78-14.71). The importance of being able "to access new, effective treatments against diseases that do not have any treatment available" was ranked as the most important factor to consider when using ES cells for drug development. CONCLUSION: Most respondents are positive about using ES cells for drug development, and making effective treatments accessible to those who do not have any. However, these attitudes are influenced by the specific disorder that the drug development is intended for, as well as the religious views and perceived moral status of the early embryo.

Trial of Deferiprone in Parkinson's Disease.

BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).

Patients' views on using human embryonic stem cells to treat Parkinson's disease: an interview study.

BACKGROUND: Human embryonic stem cells (hESC) as a source for the development of advanced therapy medicinal products are considered for treatment of Parkinson's disease (PD). Research has shown promising results and opened an avenue of great importance for patients who currently lack a disease modifying therapy. The use of hESC has given rise to moral concerns and been the focus of often heated debates on the moral status of human embryos. Approval for marketing is still pending. OBJECTIVE: To Investigate the perspectives and concerns of patients with PD, patients being the directly concerned stakeholders in the ethical discussion. METHODS: Qualitative semi-structured interviews related to this new therapy in seventeen patients from two Swedish cities. RESULTS: The participants expressed various interests related to the use of human embryos for development of medicinal therapies; however, overall, they were positive towards the use of hESC for treatment of PD. It was deemed important that the donating woman or couple made the choice to donate embryos voluntarily. Furthermore, there were concerns that the industry does not always prioritise the patient over profit; thus, transparency was seen as important.

Levodopa-entacapone-carbidopa intestinal gel infusion in advanced Parkinson's disease: real-world experience and practical guidance.

As Parkinson's disease (PD) progresses, treatment needs to be adapted to maintain symptom control. Once patients develop advanced PD, an optimised regimen of oral and transdermal medications may no longer provide adequate relief of OFF periods and motor complications can emerge. At this point, patients may wish to consider a device-aided therapy (DAT) that provides continuous dopaminergic stimulation to help overcome these issues. Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion is a recently developed DAT option. The aim of this article is twofold: (1) to give an overview of the pharmacokinetics of LECIG infusion and clinical experience to date of its use in patients with advanced PD, including real-world data and patient-reported outcomes from a cohort of patients treated in Sweden, the first country where it was introduced, and (2) based on that information to provide practical guidance for healthcare teams starting patients on LECIG infusion, whether they are transitioning from oral medications or from other DATs, including recommendations for stepwise dosing calculation and titration. In terms of clinical efficacy, LECIG infusion has been shown to have a similar effect on motor function to standard levodopa-carbidopa intestinal gel (LCIG) infusion but, due to the presence of entacapone in LECIG, the bioavailability of levodopa is increased such that lower overall levodopa doses can be given to achieve therapeutically effective plasma concentrations. From a practical standpoint, LECIG infusion is delivered using a smaller cartridge and pump system than LCIG infusion. In addition, for patients previously treated with LCIG infusion who have an existing percutaneous endoscopic transgastric jejunostomy (PEG-J) system, this is compatible with the LECIG infusion system. As it is a relatively new product, the long-term efficacy and safety of LECIG infusion remain to be established; however, real-world data will continue to be collected and analysed to provide this information and help inform future clinical decisions.

Toward Improved Treatment and Empowerment of Individuals With Parkinson Disease: Design and Evaluation of an Internet of Things System.

BACKGROUND: Parkinson disease (PD) is a chronic degenerative disorder that causes progressive neurological deterioration with profound effects on the affected individual's quality of life. Therefore, there is an urgent need to improve patient empowerment and clinical decision support in PD care. Home-based disease monitoring is an emerging information technology with the potential to transform the care of patients with chronic illnesses. Its acceptance and role in PD care need to be elucidated both among patients and caregivers. OBJECTIVE: Our main objective was to develop a novel home-based monitoring system (named EMPARK) with patient and clinician interface to improve patient empowerment and clinical care in PD. METHODS: We used elements of design science research and user-centered design for requirement elicitation and subsequent information and communications technology (ICT) development. Functionalities of the interfaces were the subject of user-centric multistep evaluation complemented by semantic analysis of the recorded end-user reactions. The ICT structure of EMPARK was evaluated using the ICT for patient empowerment model. RESULTS: Software and hardware system architecture for the collection and calculation of relevant parameters of disease management via home monitoring were established. Here, we describe the patient interface and the functional characteristics and evaluation of a novel clinician interface. In accordance with our previous findings with regard to the patient interface, our current results indicate an overall high utility and user acceptance of the clinician interface. Special characteristics of EMPARK in key areas of interest emerged from end-user evaluations, with clear potential for future system development and deployment in daily clinical practice. Evaluation through the principles of ICT for patient empowerment model, along with prior findings from patient interface evaluation, suggests that EMPARK has the potential to empower patients with PD. CONCLUSIONS: The EMPARK system is a novel home monitoring system for providing patients with PD and the care team with feedback on longitudinal disease activities. User-centric development and evaluation of the system indicated high user acceptance and usability. The EMPARK infrastructure would empower patients and could be used for future applications in daily care and research.

Pharmacokinetics of Intravenously (DIZ101), Subcutaneously (DIZ102), and Intestinally (LCIG) Infused Levodopa in Advanced Parkinson Disease.

BACKGROUND AND OBJECTIVES: Intestinal levodopa/carbidopa gel infusion (LCIG) is superior to oral treatment in advanced Parkinson's disease. The primary objectives of this trial were to investigate if continuous subcutaneous or intravenous infusion with a continuously buffered acidic levodopa/carbidopa solution yields steady state plasma concentrations of levodopa that are equivalent in magnitude, and non-inferior in variability, to those obtained with LCIG in patients with advanced Parkinson's disease. METHODS: A concentrated acidic levodopa/carbidopa (8:1) solution buffered continuously and administered intravenously (DIZ101) or subcutaneously (DIZ102) was compared with an approved intestinal levodopa/carbidopa gel (LCIG) in a randomized, 3-period cross-over, open-label multicenter trial. Formulations were infused for 16h to patients with Parkinson's disease who were using LCIG as their regular treatment. Patients were recruited at several university neurology clinics but came to the same phase I unit for treatment. Pharmacokinetic variables and safety including dermal tolerance are reported. The primary outcomes were bioequivalence and non-inferior variability of DIZ101 and DIZ102 versus LCIG with respect to levodopa plasma concentrations. RESULTS: With dosing adjusted to estimated bioavailability, DIZ101 and DIZ102 produced levodopa plasma levels within standard bioequivalence limits when compared to LCIG in the 18 participants that received all treatments. While the levodopa bioavailability for DIZ102 was complete, it was 80% for LCIG. Therapeutic concentrations of levodopa were reached as quickly with subcutaneous administration of DIZ102 as with LCIG and remained stable throughout the infusions. Due to poor uptake with LCIG, carbidopa levels in plasma were higher with DIZ101 and DIZ102 than with the former. All individuals receiving any of the treatments (n=20) were included in the evaluation of safety and tolerability. Reactions at the infusion sites were mild and transient. DISCUSSION: It is feasible to rapidly achieve high and stable levodopa concentrations by means of continuous buffering of a subcutaneously administered acidic levodopa/carbidopa containing solution. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03419806. Registration first posted 5 Feb 2018, first patient enrolled 16 Feb 2018. Link to registration.

Composite attenuation correction method using a 68Ge-transmission multi-atlas for quantitative brain PET/MR.

In positron emission tomography (PET), 68Ge-transmission scanning is considered the gold standard in attenuation correction (AC) though not available in current dual imaging systems. In this experimental study we evaluated a novel AC method for PET/magnetic resonance (MR) imaging which is essentially based on a composite database of multiple 68Ge-transmission maps and T1-weighted (T1w) MR image-pairs (composite transmission, CTR-AC). This proof-of-concept study used retrospectively a database with 125 pairs of co-registered 68Ge-AC maps and T1w MR images from anatomical normal subjects and a validation dataset comprising dynamic [11C]PE2I PET data from nine patients with Parkinsonism. CTR-AC maps were generated by non-rigid image registration of all database T1w MRI to each subject's T1w, applying the same transformation to every 68Ge-AC map, and averaging the resulting 68Ge-AC maps. [11C]PE2I PET images were reconstructed using CTR-AC and a patient-specific 68Ge-AC map as the reference standard. Standardized uptake values (SUV) and quantitative parameters of kinetic analysis were compared, i.e., relative delivery (R1) and non-displaceable binding potential (BPND). CTR-AC showed high accuracy for whole-brain SUV (mean %bias ± SD: 0.5 ± 3.5%), whole-brain R1 (-0.1 ± 3.2%), and putamen BPND (3.7 ± 8.1%). SUV and R1 precision (SD of %bias) were modest and lowest in the anterior cortex, with an R1 %bias of -1.1 ± 6.4%). The prototype CTR-AC is capable of providing accurate MRAC-maps with continuous linear attenuation coefficients though still experimental. The method's accuracy is comparable to the best MRAC methods published so far, both in SUV and as found for ZTE-AC in quantitative parameters of kinetic modelling.

Optimizing Treatment of Parkinson's Disease.

The holy grail of therapy in Parkinson's disease (PD) is treatment that would halt the disease process or restore the degenerated neuronal circuits [...].

Higher levels of neurofilament light chain and total tau in CSF are associated with negative outcome after shunt surgery in patients with normal pressure hydrocephalus.

BACKGROUND: Lumbar punctures are a common examination in the work-up of patients with idiopathic normal pressure hydrocephalus (iNPH) and cerebrospinal fluid (CSF) biomarkers should therefore be available for use in selection of shunt candidates. The aim of this study was to investigate if CSF biomarkers are associated with outcome after shunt surgery alone or in combination with comorbidity and imaging markers, and investigate associations between CSF biomarkers and symptoms. METHODS: Preoperative CSF biomarkers were analyzed in 455 patients operated with shunt surgery for iNPH at a single center during 2011-2018. Symptoms before and 12 months after shunt surgery were graded with the Swedish iNPH scale. Neurofilament light chain protein (NfL), total tau (T-tau), phosphorylated tau (P-tau) and amyloid beta1-42 (Aß1-42) CSF levels were measured. Evans' index and disproportionately enlarged subarachnoid space hydrocephalus were measured on preoperative CT-scans. Preoperative evaluation and follow-up 12 months after shunt surgery were available in 376 patients. RESULTS: Higher levels of NfL and T-tau were associated with less improvement after shunt surgery (ß = - 3.10, p = 0.016 and ß = - 2.45, p = 0.012, respectively). Patients whose symptoms deteriorated after shunt surgery had higher preoperative levels of NfL (1250 ng/L [IQR:1020-2220] vs. 1020 [770-1649], p < 0.001) and T-tau (221 ng/L [IQR: 159-346] vs. 190 [135-261], p = 0.0039) than patients with postoperative improvement on the iNPH scale. Among the patients who improved ≥ 5 levels on the iNPH scale (55%), NfL was abnormal in 22%, T-tau in 14%, P-tau in 6% and Aß1-42 in 45%, compared with normal reference limits. The inclusion of CSF biomarkers, imaging markers and comorbidity in multivariate predictive Orthogonal Projections to Latent Structures (OPLS) models to did not improve predictability in outcome after shunt surgery. CONCLUSIONS: Higher levels of T-tau and NfL were associated with a less favorable response to shunt surgery, suggesting a more active neurodegeneration in this group of patients. However, CSF levels of these biomarkers can be elevated also in patients who respond to shunt surgery. Thus, none of these CSF biomarkers, alone or used in combination, are suitable for excluding patients from surgery.

Midbrain area and the hummingbird sign from brain MRI in progressive supranuclear palsy and idiopathic normal pressure hydrocephalus.

BACKGROUND AND PURPOSE: The main radiological finding in progressive supranuclear palsy (PSP) is reduced midbrain volume. Both qualitative (e.g., hummingbird sign) and quantitative (e.g., area measurements) markers have been noted. Recent studies have shown a similar reduction also in idiopathic normal pressure hydrocephalus (iNPH). The purpose was to investigate the reliability and accuracy of these markers in discriminating PSP from iNPH and controls. METHODS: Eight neuroradiologists viewed sagittal MR images of the midbrain from 104 subjects: 26 PSP patients, 40 iNPH patients, and 38 healthy controls. They visually assessed whether the hummingbird sign was present or not, grading their confidence from 1 to 5. Assessments were translated into a score between +5 and -5: from maximum confidence of presence to maximum confidence of absence. A positive median score was considered to indicate hummingbird sign. Sagittal midbrain area was manually measured in each subject. RESULTS: Seventy-seven percent of PSP patients, 65% of iNPH, and 3% of controls were visually assessed as having the hummingbird sign. Manually measured midbrain area also showed overlap between PSP and iNPH. Regarding discrimination of PSP patients, midbrain area measurements, using a cutoff of 90 mm2 , yielded a higher area under the curve (AUC = 0.86) than visual assessment scores (AUC = 0.83), and higher reliability. CONCLUSIONS: Measuring sagittal midbrain area is more accurate and reliable than visual assessment. Due to significant overlap in appearance, a midbrain with a hummingbird sign or reduced sagittal area should raise the suspicion of PSP only after other signs of iNPH have been considered.

Pain, disease severity and associations with individual quality of life in patients with motor neuron diseases.

BACKGROUND: Up to 85% of people with motor neuron disease (MND) report pain, but whether pain has negative impact on quality of life is unclear. The aim was to study associations between pain, disease severity and individual quality of life (IQOL) in patients with MND. METHODS: In this cross sectional study, 61 patients were recruited from four multidisciplinary teams in Sweden, whereof 55 responded to the pain measure (The Brief Pain Inventory - Short form) and were included in the main analyses. Disease severity was measured with the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Version, and individual quality of life was measured with a study-specific version of the Schedule for the Evaluation of Individual Quality of Life - Direct Weighting. RESULTS: Forty-one (74%) of the participants who answered BPI-SF (n = 55) reported pain. Thirty-nine (71%) of those reported pain during the past 24 h. The severity of pain was on average moderate, with eight participants (14%) reporting severe pain (PSI ≥ 7). Satisfaction with IQOL for the entire sample was good (scale 1-7, where 1 equals poor quality of life): median 5, interquartile range (IQR) 2.75 and there was no difference in satisfaction with IQOL between those reporting pain/not reporting pain (median 5, IQR 2/median 5, IQR 3.5, Mann-Whitney U = 249, p = 0.452). There was neither any correlation between pain severity and satisfaction with IQOL, nor between disease severity and satisfaction with IQOL. CONCLUSIONS: The results add to the hypothesis that associations between non-motor symptoms such as pain prevalence and pain severity and IQOL in MND are weak. Pain prevalence was high and the results pointed to that some participants experienced high pain severity, which indicate that pain assessments and pain treatments tailored to the specific needs of the MND population should be developed and scientifically evaluated.

Personalized Medicine Approach in Treating Parkinson's Disease, Using Oral Administration of Levodopa/Carbidopa Microtablets in Clinical Practice.

BACKGROUND: The most effective symptomatic treatment in Parkinson's disease (PD) is levodopa in standard doses. However, as the disease progresses, there may be a need for a more personalized approach and fine tuning, in accordance with the patients' needs. This study aims to evaluate the individual experience of levodopa/carbidopa 5/1.25 mg microtablets (LC-5) in clinical practice with respect to efficacy, tolerability, and usability. The method used was as follows: patients answered a questionnaire concerning the effect and usability of LC-5, and their medical records were reviewed. Regarding results, thirty-five survey responses were obtained, and 29 patients' medical records were reviewed. The LC-5 dose dispenser usability was generally rated positively and facilitated medication adherence. The majority (85%) of patients reported symptom improvement while using LC-5, compared with previous standard treatments. These results suggest that LC-5 therapy is generally well-tolerated, with favorable patient-reported efficacy and user friendliness, as well as the possibility for an individualized, fine-tuned PD treatment. Further studies with a prospective design and larger study population are needed to confirm the results.