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Background: Open-HART was an open-label extension of HART, a randomized, double-blind, placebo-controlled study of pridopidine in Huntington disease (HD). Previously, we reported safety and exploratory efficacy data after 36 months of treatment with pridopidine 45 mg twice daily. In the interim, emerging data suggests pridopidine may have neuroprotective effects mediated by sigma-1 receptor agonism. Objective: To report additional safety and exploratory efficacy data for continued open-label use of 45 mg BID pridopidine at 48 and 60 months. Methods: Patients in Open-HART were followed up to or greater than 60 months. Adverse events, concomitant medications, vital signs, laboratory values, and ECG data were monitored. Rates of decline in total functional capacity (TFC) and total motor score (TMS) over 60 months were evaluated in an exploratory analysis and compared between Open-HART and placebo recipients from the 2CARE trial. To account for missing data, sensitivity analyses were performed. Results: Of the original Open-HART baseline cohort (N = 118), 40 remained in the study at 48 months and 33 at 60 months. Pridopidine remained safe and well tolerated over the 60-month interval. TFC and TMS at 48 and 60 months remained stable, showing less decline at these timepoints compared to historical placebo controls from the 2CARE trial. TFC differences at 48 and 60 months observed remained nominally significant after sensitivity analysis. Conclusion: The 45 mg BID pridopidine dosage remained safe and tolerable over 60 months. Exploratory analyses show TFC and TMS stability at 48 and 60 months, in contrast to placebo historical controls from the 2CARE trial. Results are consistent with data reported from the recent Phase 2 PRIDE-HD trial showing less functional decline in the pridopidine 45 mg BID treated group at 52 weeks. [ABSTRACT FROM AUTHOR]

Aims: SD‐1077, a selectively deuterated precursor of dopamine (DA) structurally related to L‐3,4‐dihydroxyphenylalanine (L‐DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD‐1077. Methods: Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD‐1077 dose were compared to 150 mg L‐DOPA, each in combination with 37.5 mg carbidopa (CD) in a double‐blind, two‐period, crossover study in healthy volunteers (n = 16). Results: Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD‐1077 vs. L‐DOPA for Cmax, AUC0–t, and AUC0–inf were 88.4 (75.9–103.1), 89.5 (84.1–95.3), and 89.6 (84.2–95.4), respectively. Systemic exposure to DA was significantly higher after SD‐1077/CD compared to that after L‐DOPA/CD, with GMRs (90% CI) of 1.8 (1.45–2.24; P = 0.0005) and 2.06 (1.68–2.52; P < 0.0001) for Cmax and AUC0–t and a concomitant reduction in the ratio of 3,4‐dihydroxyphenylacetic acid/DA confirming slower metabolic breakdown of DA by monoamine oxidase (MAO). There were increases in systemic exposures to metabolites of catechol O‐methyltransferase (COMT) reaction, 3‐methoxytyramine (3‐MT) and 3‐O‐methyldopa (3‐OMD) with GMRs (90% CI) for SD‐1077/CD to L‐DOPA/CD for 3‐MT exposure of 1.33 (1.14–1.56; P = 0.0077) and 1.66 (1.42–1.93; P < 0.0001) for Cmax and AUC0–t, respectively and GMRs (90% CI) for 3‐OMD of 1.19 (1.15, 1.23; P < 0.0001) and 1.31 (1.27, 1.36; P < 0.0001) for Cmax and AUC0–t. SD‐1077/CD exhibited comparable tolerability and safety to L‐DOPA/CD. Conclusions: SD‐1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L‐DOPA/CD combination. A single dose of SD‐1077 is safe for further clinical development in Parkinson's disease patients. [ABSTRACT FROM AUTHOR]

Background: Open-HART is an open-label extension of HART, a randomized, placebo-controlled, dose-ranging, parallelgroup study. Objective: To evaluate safety and exploratory efficacy of open-label pridopidine over 36 months in subjects with Huntington's disease (HD). Methods: Open-HART subjects were treated with pridopidine 45 mg twice daily (BID). After initial evaluation by telephone (Week 1) and in person (Month 1), in-person visits occurred every 3 months, alternating between safety and clinical visits (safety plus Unified Huntington's Disease Rating Scale [UHDRS] assessment). The UHDRS was performed for pre-specified analysis as a secondary outcome measure. Adverse events (AEs), laboratory values and electrocardiography were monitored throughout. Results: Most subjects (89%) reported at least one AE, with 30% experiencing treatment-related AEs. The most common AEs during the first year were falls (12.7%), anxiety (9.3%), insomnia (8.5%), irritability (6.8%) and depression (5.9%). Ninety-nine percent of subjects took concomitant medications. Two seizures were reported as AEs. No arrhythmias or suicide attempts were reported. Five deaths occurred, all considered treatment unrelated. Secondary exploratory analyses of subjects on pridopidine demonstrated motor deterioration (as measured by the UHDRS total motor score) consistent with HD's natural history, as shown in large observational studies. A post-hoc, exploratory analysis of TFC performance compared to placebo groups from other long-term HD studies demonstrated no significant effect for pridopidine on TFC progression after correction for multiple comparisons. Conclusions: Pridopidine 45 mg BID was generally safe and tolerable in HD subjects over 36 months. TMS declined in a manner consistent with the known natural history of HD. [ABSTRACT FROM AUTHOR]

Introduction Diagnostic effectiveness of Ioflupane I 123 injection (DaTSCAN™, DaTscan™, or [123I]FPCIT or ioflupane [123I]) SPECT imaging, was assessed in patients with clinically uncertain parkinsonian syndrome (CUPS). Methods We investigated the association between subject's Hoehn & Yahr (H&Y) stage, Mini-Mental State Examination (MMSE), age, and motor symptom subgroups and diagnostic performance of ioflupane [123I] imaging. Phase 4 study data were used to calculate sensitivity, specificity, positive and negative predictive value, and accuracy in 92 CUPS subjects, using 1-year clinical diagnosis after ioflupane [123I] imaging as reference standard. Results Diagnostic effectiveness of ioflupane [123I] imaging was high in all subgroups: 91% to 100% for H&Y low (<2) and high (⩾2) stage subjects; 93% to 96% for MMSE low (<29) or high (⩾29) scores; 91% to100% in both age subgroups (younger [<68] and older [⩾68]); and 92% to 100% in subjects with both tremor dominant and balanced motor signs. Specificity of ioflupane [123I] imaging for bradykinetic rigid or posturally (BRP) unstable motor subtype was lower, but better than for baseline clinical diagnosis. Conclusions Strongest diagnostic performance of ioflupane [123I] imaging for clinical diagnosis of Parkinson's syndrome (PS) or non-PS was associated with tremor and balanced motor dominance rather than with BRP dominance. High diagnostic effectiveness of ioflupane [123I] imaging and favourable performance relative to final clinical diagnosis at 1 year post-scan in subjects with CUPS was demonstrated. This study suggests that the diagnostic performance of ioflupane [123I] imaging in CUPS remains high at all stages of disease, including early stage, and across both age groups and cognitive state (MMSE). [ABSTRACT FROM AUTHOR]

Objectives: To pool clinical trials of similar design to assess overall sensitivity and specificity of ioflupane I123 injection (DaTSCAN or ioflupane (123I)) to detect or exclude a striatal dopaminergic deficit disorder (SDDD), such as parkinsonian syndrome and dementia with Lewy bodies. Design: Pooled analysis of three phase 3 and one phase 4 clinical trials. These four trials were selected because they were the four studies used for the US new drug application to the Food and Drug Administration (FDA). Setting: Multicentre, open-label, non-randomised. Participants: Patients with either a movement disorder or dementia, and healthy volunteers. Interventions: Ioflupane (123I) was administered. Outcome measures: Images were assessed by panels of 3-5 blinded experts and/or on-site nuclear medicine physicians, classified as normal or abnormal and compared with clinical diagnosis (reference standard) to determine sensitivity and specificity. Results: Pooling the four studies, 928 participants were enrolled, 849 were dosed and 764 completed their study. Across all studies, when images were assessed by on-site readers, ioflupane (123I) diagnostic effectiveness had an overall (95% CI) sensitivity of 91.9% (88.7% to 94.5%) and specificity of 83.6% (78.7% to 87.9%). When reads were conducted blindly by a panel of independent experts, the overall sensitivity was 88.7% (86.8% to 90.4%) and specificity was 91.2% (89.0% to 93.0%). Conclusions: In this pooled analysis, the visual assessment of ioflupane (123I) images provided high levels of sensitivity and specificity in detecting the presence/absence of an SDDD. Ioflupane (123I) imaging has the potential to improve diagnostic accuracy in patients with signs and symptoms of a movement disorder and/or dementia. Trial registration number: NCT00209456. [ABSTRACT FROM AUTHOR]

The diagnosis of movement disorders including Parkinson's disease (PD) and essential tremor is determined through clinical assessment. The difficulty with diagnosis of early PD has been highlighted in several recent clinical trials. Studies have suggested relatively high clinical diagnostic error rates for PD and essential tremor. This review was undertaken to clarify the utility of DaT-SPECT imaging with (123I)ioflupane (DaTSCAN or DaTscan or (123I)FP-CIT) in assisting practitioners in their clinical decision making by visualising the dopamine transporter in parkinsonian cases. In some patients with suspected parkinsonian syndromes, SPECT imaging with (123I)ioflupane is useful to assist in the diagnosis and to help guide prognosis and treatment decisions, including avoiding medications that are unlikely to provide benefit. Clinicians ordering (123I)ioflupane SPECT should be aware of its limitations and pitfalls and should order scans when there is diagnostic uncertainty or when the scan will be helpful in clinical decision making. [ABSTRACT FROM AUTHOR]

Background: An accurate diagnosis is important for timely and adequate treatment in patients with clinically uncertain parkinsonian syndrome (CUPS). Objective: The objective of this study was to assess safety and changes in clinical management, diagnosis and quality of life (QoL) at 4 and 12 weeks following DaTscan™ (ioflupane [123I] injection) imaging in patients with CUPS. Methods: This randomized, open-label, single-dose, multicenter trial was carried out in patients with CUPS who were randomized to either a DaTscan imaging group or to a control group without imaging. The main outcome measures were the proportions of patients with changes in clinical management and diagnosis from baseline through to 12 weeks after DaTscan. A total of 19 university hospital centers in Europe and the USA participated in the study. There were 267 patients enrolled and randomized (131 DaTscan, 136 control). Results: Significantly more DaTscan patients had changes in clinical management after 12 weeks (p = 0.004) compared to the control group, and significantly more DaTscan patients had changes in diagnosis at 4 weeks and at 12 weeks (both p < 0.001) compared to control patients. No significant difference in total score for QoL was observed between groups during the study duration. DaTscan was safe and well-tolerated. No deaths, serious adverse events (AEs) or withdrawals due to AEs occurred during the study. One patient had a headache following treatment with a suspected relationship to DaTscan. Conclusion: DaTscan imaging significantly affected the clinical management and diagnosis of patients with CUPS. DaTscan is safe and well-tolerated and is a useful adjunct to differential diagnosis of CUPS. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Examines the multichemical proton magnetic resonance spectroscopy profile of the human brain for several age groups. Increase of total chemical concentration in the prefrontal and sensorimotor cortices; Hypothesis on the level of brain chemicals; Relation of brain chemicals with creatine in measuring chemical concentration.

The article presents the authors views on finding causal relationship between Parkinson's disease (PD) with depressive symptoms by dopamine transporter (DaT) imaging with iodine-123-fluoropropyl (FP)-carbomethoxy-3 β-(4-iodophenyltropane) (CIT). He states that motor impairment assessed by the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) and depressive symptoms assessed by the Beck Depression Inventory (BDI) both correlated negatively with DaT uptake.

Previous studies have demonstrated the feasibility and promise of wearable sensors as objective measures of motor impairment in Parkinson disease and essential tremor. However, there are few published studies that have examined such an application in Huntington disease (HD). This report provides an evaluation of the potential to objectively quantify chorea in HD patients using wearable sensor data. Data were derived from a substudy of the phase 2 Open-PRIDE-HD study, where 17 patients were screened and 15 patients enrolled in the substudy and ultimately 10 patients provided sufficient wearable sensor data. The substudy was designed to provide high-resolution data to inform design of predictive algorithms for chorea quantification. During the entire course of the 6-month study, in addition to chorea ratings from 18 in-clinic assessments, 890 home assessments, and 1,388 responses to daily reminders, 33,000 h of high-resolution accelerometer data were captured continuously from wearable smartwatches and smartphones. Despite its limited sample size, our study demonstrates that arm chorea can be characterized using accelerometer data during static assessments. Nonetheless, the small sample size limits the generalizability of the model. The sensor-based model can quantify the chorea level with high correlation to the chorea severity reported by both clinicians and patients. In addition, our analysis shows that the chorea digital signature varies between patients. This work suggests that digital wearable sensors have the potential to support clinical development of medications in patients with movement disorders, such as chorea. However, additional data would be needed from a larger number of HD patients with a full range of chorea severity (none to severe) with and without intervention to validate this potentially predictive technology., Competing Interests: M.F. Gordon, I.D. Grachev, P.S. Loupe, S. Fine, L. Navon-Perry, N. Gross, S. Papapetropoulos, J.-M. Savola, and M.R. Hayden are or were Teva Pharmaceutical Industries employees during the course of this study. I. Mazeh and Y. Dolan are employees of Intel. R. Reilmann is founding director and owner of the George Huntington Institute, a private research institute focused on clinical and preclinical research in HD, and QuantiMedis, a clinical research organization providing Q-Motor services in clinical trials and research. He serves as an elected member of the steering committees of the European Huntington's Disease Network and the Huntington Study Group, co-chair of the Task Force on Huntington's Disease, and member of the Task Force on Technology of the International Parkinson and Movement Disorder Society. He has provided consulting services, advisory board functions, clinical trial services, Q-Motor analyses, or lectures for Actelion Pharmaceuticals, Amarin Neuroscience, AOP Orphan Pharmaceuticals, the Cure Huntington Disease Initiative Foundation, Desitin, Hoffmann-La Roche, Ionis Pharmaceuticals, Ipsen, Lundbeck, Link Medicine, Meda Pharma, Medivation, Mitoconix, Neurocrine Biosciences, Neurosearch, Novartis, Omeros, Pfizer, Prana Biotechnology, Prilenia Therapeutics, Raptor Pharmaceuticals, Siena Biotech, Temmler Pharma, Teva Pharmaceuticals, uniQure, Vaccinex, Wave Life Sciences, and Wyeth Pharmaceuticals. He has received grant support from the Bundesministerium für Bildung und Forschung, the Cure Huntington Disease Initiative Foundation, the Deutsche Forschungsgemeinschaft, the Deutsches Zentrum fur Neurodegeneration und Entzündung, the European Union Seventh Framework Program (EU-FP7), the European Huntington's Disease Network, the High Q Foundation, and the National Science Foundation., (Copyright © 2019 by S. Karger AG, Basel.)

Ioflupane is an analog of cocaine that binds reversibly with high affinity to the dopamine transporter (DaT) protein, a marker for presynaptic terminals in dopaminergic nigrostriatal neurons. Ioflupane (123)I Injection is also known as DaTscan or DaTSCAN ((123)I-ioflupane is also called (123)I-2-β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane or (123)I-FP-CIT). The diagnostic efficacy of DaTscan has been described elsewhere. Here, we present a comprehensive analysis of the safety of DaTscan starting from initiation of clinical development through 13 y after the date of first market approval. Safety data in the sponsor's clinical development safety database from 10 completed DaTscan clinical trials were pooled, and postapproval experience was summarized from standardized aggregate safety reports submitted to regulatory agencies. A total of 1,180 clinical trial subjects (92% of 1,284 subjects planned to receive DaTscan in the clinical trials) received DaTscan. Percentages of subjects with adverse events by category were as follows: all (22%), considered at least possibly related to DaTscan by the investigator (4%), any severe (3%), headache (4%), nausea (2%), dizziness (2%), nasopharyngitis (1%), and injection site hematoma (1%). Four percent of subjects had at least 1 serious adverse event; 5 subjects (<1%) had serious adverse events that led to death. All serious adverse events, including those that led to death, were deemed by an expert clinician to be unrelated to DaTscan. An estimated half a million market doses of DaTscan (for single use) were administered from July 2000 through the July 2013 reporting period. In postapproval safety assessment, 1 death was reported 20 d after (and unrelated to) DaTscan administration. Two spontaneously reported serious adverse drug reactions (ADRs) and 32 spontaneously reported nonserious ADRs were submitted, approximately half of which are identified in labeling. Headache (in clinical trials) and injection site pain (postapproval) were the most commonly reported events or reactions. Although adverse events were reported for 1 in 5 clinical trial subjects, most were mild and considered unrelated to DaTscan administration. Severe events were uncommon, and no serious adverse event occurring in more than 1 subject was deemed related to DaTscan administration. In postapproval experience, the frequency of ADRs spontaneously reported was less than 1 per 10,000 doses administered. Comprehensive safety data show that DaTscan was well tolerated., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: Establishing an early, accurate diagnosis is fundamental for appropriate clinical management of patients with movement disorders or dementia. Ioflupane (123)I Injection (DaTscan, (123)I-ioflupane) is an important adjunct to support the clinical diagnosis. Understanding individual-reader diagnostic performance of (123)I-ioflupane in a variety of clinical scenarios is essential., Methods: Sensitivity, specificity, interreader, and intrareader data from 5 multicenter clinical studies were reviewed. The different study designs offered an assortment of variables to assess the effects on the diagnostic performance of (123)I-ioflupane: on-site versus 3-5 blinded image readers, number of image evaluations, early/uncertain versus late/confirmed clinical diagnosis as reference standard, and subjects with movement disorders versus dementia., Results: Eight hundred eighteen subjects had individual-reader efficacy data available for analysis. In general, sensitivity and specificity were high and comparable between on-site versus blinded independent readers. In subjects with dementia, when the clinical diagnosis was made at month 12 versus baseline, specificity improved from 77.4%-91.2% to 81.6%-95.0%. In subjects with movement disorders, this effect was observed to an even greater extent, when diagnostic performance using month-18 diagnosis as a reference standard (sensitivity, 67.0%-73.7%; specificity, 75.0%-83.3%) was compared versus month-36 diagnosis (77.5%-80.3% and 90.3%-96.8%, respectively). Diagnostic performance was similar in subjects with dementia (74.4%-89.9% and 77.4%-95.0%, respectively) and subjects with movement disorders (67.0%-97.9% and 71.4%-98.4%, respectively). In most of the comparisons, between-reader agreement was very good (almost perfect), with κ ranging from 0.81 to 1.00. Within-reader agreement, measured in 1 study, was 100% for 3 blinded readers., Conclusion: Individual-reader diagnostic performance, as assessed by measuring sensitivity and specificity of (123)I-ioflupane to detect the presence or absence of striatal dopaminergic deficit, using the clinical diagnosis as a reference standard, was high in subjects with either movement disorders or dementia and was similar in on-site readers versus blinded analyses. Between- and within-reader agreements were very good (almost perfect). Longer follow-up between imaging and clinical diagnosis improved the diagnostic accuracy, most likely due to improvement in the clinical diagnosis reference standard, rather than changes in reader accuracy., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Introduction: PET imaging of amyloid-β (Aβ) in vivo holds promise for aiding in earlier diagnosis and intervention in Alzheimer's disease (AD) and mild cognitive impairment. AD-like Aβ pathology is a common comorbidity in patients with idiopathic normal pressure hydrocephalus (iNPH). Fifty patients with iNPH needing ventriculo-peritoneal shunting or intracranial pressure monitoring underwent [18F]flutemetamol PET before (N = 28) or after (N = 22) surgery. Cortical uptake of [18F]flutemetamol was assessed visually by blinded reviewers, and also quantitatively via standard uptake value ratio (SUVR) in specific neocortical regions in relation to either cerebellum or pons reference region: the cerebral cortex of (prospective studies) or surrounding (retrospective studies) the biopsy site, the contralateral homolog, and a calculated composite brain measure. Aβ pathology in the biopsy specimen (standard of truth [SoT]) was measured using Bielschowsky silver and thioflavin S plaque scores, percentage area of grey matter positive for monoclonal antibody to Aβ (4G8), and overall pathology impression. We set out to find (1) which pair(s) of PET SUVR and pathology SoT endpoints matched best, (2) whether quantitative measures of [18F]flutemetamol PET were better for predicting the pathology outcome than blinded image examination (BIE), and (3) whether there was a better match between PET image findings in retrospective vs. prospective studies., Results: Of the 24 possible endpoint/SoT combinations, the one with composite-cerebellum SUVR and SoT based on overall pathology had the highest Youden index (1.000), receiver operating characteristic area under the curve (1.000), sensitivity (1.000), specificity (1.000), and sum of sensitivity and specificity for the pooled data as well as for the retrospective and prospective studies separately (2.00, for all 3). The BIE sum of sensitivity and specificity, comparable to that for quantitation, was highest using Bielschowsky silver as SoT for all SUVRs (ipsilateral, contralateral, and composite, for both reference regions). The composite SUVR had a 100% positive predictive value (both reference regions) for the overall pathology diagnosis. All SUVRs had a 100% negative predictive value for the Bielschowsky silver result., Conclusion: Bielschowsky silver stain and overall pathology judgment showed the strongest associations with imaging results.

Parkinson's disease (PD), the second-most common neurodegenerative disease, is characterized by motor and nonmotor symptoms. PD is often misdiagnosed; inappropriate treatment due to misdiagnosis has undesired consequences, as does delayed diagnosis. Unfortunately, most people with PD receive a diagnosis only after motor symptoms have emerged, by which time 40% to 60% of dopamine neurons have already been lost. Advances in imaging techniques have provided clinicians with increasingly sophisticated tools. In 2011, the US Food and Drug Administration approved ioflupane I-123 injection (DaTscanTM) for striatal dopamine transporter visualization using single-photon emission computed tomography (SPECT) imaging, which provides an effective tool for assessing striatal dopaminergic deficiency. Among patients with suspected parkinsonian syndromes, of which PD is one, the diagnostic sensitivity and specificity of DaTscan SPECT imaging are high. In clinical studies that were part of the DaTscan new drug application, no serious drug-related adverse events reported by the 1236 participants were attributed to DaTscan. The introduction of DaTscan imaging and its utility necessitate the development of clinical recommendations for appropriate use; thus, a multidisciplinary panel of experts was convened to develop clinical criteria and algorithms to help guide clinicians and managed care organizations in the application of DaTscan SPECT imaging. Based on the consensus of this expert panel, appropriate use of DaTscan SPECT imaging includes cases where: (1) PD diagnosis is uncertain; (2) tremor of uncertain etiology is present; and (3) nonmotor and/ or supportive symptoms and features associated with PD are present but the classical motor syndrome is absent or atypical.