Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study.

PURPOSE: Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [18F] fluspidine and [18F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD. METHODS: Using [18F] fluspidine PET (300 MBq, 0-90 min), 11 male HVs (pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (pridopidine 90 mg) were investigated twice, without and 2 h after single dose of pridopidine. Using [18F] fallypride PET (200 MBq, 0-210 min), four male HVs were studied without and 2 h following pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot. RESULTS: S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%). CONCLUSIONS: Our PET findings indicate that at clinically relevant single dose of 90 mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine's mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.

Additional Safety and Exploratory Efficacy Data at 48 and 60 Months from Open-HART, an Open-Label Extension Study of Pridopidine in Huntington Disease.

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.

Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study.

BACKGROUND: Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington's disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability. METHODS: PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged ≥21 years) with Huntington's disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA). Eligible patients had clinical onset after age 18 years, 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, motor symptoms (Unified Huntington's Disease Rating Scale total motor score [UHDRS-TMS] ≥25 points), and reduced independence (UHDRS independence score ≤90%). Patients were randomly assigned (1:1:1:1:1) with centralised interactive-response technology to receive one of four doses of pridopidine (45, 67·5, 90, or 112·5 mg) or placebo orally twice a day for 52 weeks. Randomisation was stratified within centres by neuroleptic drug use. The primary efficacy endpoint was change in the UHDRS-TMS from baseline to 26 weeks, which was assessed in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment (full analysis set). Participants and investigators were masked to treatment assignment. This trial is registered with EudraCT (2013-001888-23) and ClinicalTrials.gov (NCT02006472). FINDINGS: Between Feb 13, 2014, and July 5, 2016, 408 patients were enrolled and randomly assigned to receive placebo (n=82) or pridopidine 45 mg (n=81), 67·5 mg (n=82), 90 mg (n=81), or 112·5 mg (n=82) twice daily for 26 weeks. The full analysis set included 397 patients (81 in the placebo group, 75 in the 45 mg group, 79 in the 67·5 mg group, 81 in the 90 mg group, and 81 in the 112·5 mg group). Pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared with placebo at any dose. The most frequent adverse events across all groups were diarrhoea, vomiting, nasopharyngitis, falls, headache, insomnia, and anxiety. The most common treatment-related adverse events were insomnia, diarrhoea, nausea, and dizziness. Serious adverse events occurred in the pridopidine groups only and were most frequently falls (n=5), suicide attempt (n=4), suicidal ideation (n=3), head injury (n=3), and aspiration pneumonia (n=3). No new safety or tolerability concerns emerged in this study. One death in the pridopidine 112·5 mg group due to aspiration pneumonia was considered to be possibly related to the study drug. INTERPRETATION: Pridopidine did not improve the UHDRS-TMS at week 26 compared with placebo and, thus, the results of secondary or tertiary analyses in previous trials were not replicated. A potentially strong placebo effect needs to be ruled out in future studies. FUNDING: Teva Pharmaceutical Industries.

Quantification of Motor Function in Huntington Disease Patients Using Wearable Sensor Devices.

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.

Characterizing patient compliance over six months in remote digital trials of Parkinson's and Huntington disease.

BACKGROUND: A growing number of clinical trials use various sensors and smartphone applications to collect data outside of the clinic or hospital, raising the question to what extent patients comply with the unique requirements of remote study protocols. Compliance is particularly important in conditions where patients are motorically and cognitively impaired. Here, we sought to understand patient compliance in digital trials of two such pathologies, Parkinson's disease (PD) and Huntington disease (HD). METHODS: Patient compliance was assessed in two remote, six-month clinical trials of PD (n = 51, Clinician Input Study funded by the Michael J. Fox Foundation for Parkinson's Research) and HD (n = 17, sponsored by Teva Pharmaceuticals). We monitored four compliance metrics specific to remote studies: smartphone app-based medication reporting, app-based symptoms reporting, the duration of smartwatch data streaming except while charging, and the performance of structured motor tasks at home. RESULTS: While compliance over time differed between the PD and HD studies, both studies maintained high compliance levels for their entire six month duration. None (- 1%) to a 30% reduction in compliance rate was registered for HD patients, and a reduction of 34 to 53% was registered for the PD study. Both studies exhibited marked changes in compliance rates during the initial days of enrollment. Interestingly, daily smartwatch data streaming patterns were similar, peaking around noon, dropping sharply in the late evening hours around 8 pm, and having a mean of 8.6 daily streaming hours for the PD study and 10.5 h for the HD study. Individual patients tended to have either high or low compliance across all compliance metrics as measured by pairwise correlation. Encouragingly, predefined schedules and app-based reminders fulfilled their intended effect on the timing of medication intake reporting and performance of structured motor tasks at home. CONCLUSIONS: Our findings suggest that maintaining compliance over long durations is feasible, promote the use of predefined app-based reminders, and highlight the importance of patient selection as highly compliant patients typically have a higher adherence rate across the different aspects of the protocol. Overall, these data can serve as a reference point for the design of upcoming remote digital studies. TRIAL REGISTRATION: Trials described in this study include a sub-study of the Open PRIDE-HD Huntington's disease study (TV7820-CNS-20016), which was registered on July 7th, 2015, sponsored by Teva Pharmaceuticals Ltd., and registered on Clinicaltrials.gov as NCT02494778 and EudraCT as 2015-000904-24 .

Pharmacokinetics, metabolism and safety of deuterated L-DOPA (SD-1077)/carbidopa compared to L-DOPA/carbidopa following single oral dose administration in healthy subjects.

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.

Safety and Exploratory Efficacy at 36 Months in Open-HART, an Open-Label Extension Study of Pridopidine in Huntington's Disease.

BACKGROUND: Open-HART is an open-label extension of HART, a randomized, placebo-controlled, dose-ranging, parallel-group 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.

Phase 3 trial of flutemetamol labeled with radioactive fluorine 18 imaging and neuritic plaque density.

IMPORTANCE: In vivo imaging of brain ß-amyloid, a hallmark of Alzheimer disease, may assist in the clinical assessment of suspected Alzheimer disease. OBJECTIVE: To determine the sensitivity and specificity of positron emission tomography imaging with flutemetamol injection labeled with radioactive fluorine 18 to detect ß-amyloid in the brain using neuropathologically determined neuritic plaque levels as the standard of truth. DESIGN, SETTING, AND PARTICIPANTS: Open-label multicenter imaging study that took place at dementia clinics, memory centers, and hospice centers in the United States and England from June 22, 2010, to November 23, 2011. Participants included terminally ill patients who were 55 years or older with a life expectancy of less than 1 year. INTERVENTIONS: Flutemetamol injection labeled with radioactive fluorine 18 (Vizamyl; GE Healthcare) administration followed by positron emission tomography imaging and subsequent brain donation. MAIN OUTCOMES AND MEASURES: Sensitivity and specificity of flutemetamol injection labeled with radioactive fluorine 18 positron emission tomography imaging for brain ß-amyloid. Images were reviewed without and with computed tomography scans and classified as positive or negative for ß-amyloid by 5 readers who were blind to patient information. In patients who died, neuropathologically determined neuritic plaque levels were used to confirm scan interpretations and determine sensitivity and specificity. RESULTS: Of 176 patients with evaluable images, 68 patients (38%) died during the study, were autopsied, and had neuritic plaque levels determined; 25 brains (37%) were ß-amyloid negative; and 43 brains (63%) were ß-amyloid positive. Imaging was performed a mean of 3.5 months (range, 0 to 13 months) before death. Sensitivity without computed tomography was 81% to 93% (median, 88%). Median specificity was 88%, with 4 of 5 of the readers having specificity greater than 80%. When scans were interpreted with computed tomography images, sensitivity and specificity improved for most readers but the differences were not significant. The area under the receiver operating curve was 0.90. There were no clinically meaningful findings in safety parameters. CONCLUSIONS AND RELEVANCE: This study showed that flutemetamol injection labeled with radioactive fluorine 18 was safe and had high sensitivity and specificity in an end-of-life population. In vivo detection of brain ß-amyloid plaque density may increase diagnostic accuracy in cognitively impaired patients.

Association between Hoehn and Yahr, Mini-Mental State Examination, age, and clinical syndrome predominance and diagnostic effectiveness of ioflupane I 123 injection (DaTSCAN™) in subjects with clinically uncertain parkinsonian syndromes.

INTRODUCTION: Diagnostic effectiveness of Ioflupane I 123 injection (DaTSCAN™, DaTscan™, or [123I]FP-CIT or ioflupane [(123)I]) 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 [(123)I] 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 [(123)I] imaging as reference standard. RESULTS: Diagnostic effectiveness of ioflupane [(123)I] 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 [(123)I] 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 [(123)I] 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 [(123)I] 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 [(123)I] imaging in CUPS remains high at all stages of disease, including early stage, and across both age groups and cognitive state (MMSE).

Is ioflupane I123 injection diagnostically effective in patients with movement disorders and dementia? Pooled analysis of four clinical trials.

OBJECTIVES: To pool clinical trials of similar design to assess overall sensitivity and specificity of ioflupane I123 injection (DaTSCAN or ioflupane ((123)I)) 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 ((123)I) 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 ((123)I) 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 ((123)I) images provided high levels of sensitivity and specificity in detecting the presence/absence of an SDDD. Ioflupane ((123)I) 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.

Safety analysis of 10 clinical trials and for 13 years after first approval of ioflupane 123I injection (DaTscan).

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-ß-carbomethoxy-3ß-(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.

Individual-reader diagnostic performance and between-reader agreement in assessment of subjects with Parkinsonian syndrome or dementia using 123I-ioflupane injection (DaTscan) imaging.

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.

Effective and efficient diagnosis of parkinsonism: the role of dopamine transporter SPECT imaging with ioflupane I-123 injection (DaTscan™).

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.

Diagnostic effectiveness of quantitative [¹8F]flutemetamol PET imaging for detection of fibrillar amyloid ß using cortical biopsy histopathology as the standard of truth in subjects with idiopathic normal pressure hydrocephalus.

INTRODUCTION: PET imaging of amyloid-ß (Aß) in vivo holds promise for aiding in earlier diagnosis and intervention in Alzheimer's disease (AD) and mild cognitive impairment. AD-like Aß 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. Aß 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 Aß (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.

Prospective flutemetamol positron emission tomography and histopathology in normal pressure hydrocephalus.

UNLABELLED: BACKGOUND/OBJECTIVE: To determine the level of association between uptake of the amyloid positron emission tomography (PET) imaging agent [(18)F]flutemetamol and the level of amyloid-ß measured by immunohistochemical and histochemical staining in a frontal cortical region biopsy site. METHODS: Seventeen patients with probable normal pressure hydrocephalus (NPH) underwent prospective [(18)F]flutemetamol PET and subsequent frontal cortical brain biopsy during ventriculoperitoneal shunting. Tissue amyloid-ß was evaluated using the monoclonal antibody 4G8, thioflavin S and Bielschowsky silver stain. RESULTS: Four of the 17 patients (23.5%) had amyloid-ß pathology based on the overall pathology read and also showed increased [(18)F]flutemetamol uptake. [(18)F]Flutemetamol standardized uptake values from the biopsy site were significantly associated with biopsy specimen amyloid-ß levels (Pearson's r = 0.67; p = 0.006). There was also good correlation between the biopsy specimen amyloid-ß level and uptake of [(18)F]flutemetamol in the region contralateral to the biopsy site (r = 0.67; p = 0.006), as well as with composite cortical [(18)F]flutemetamol uptake (r = 0.65; p = 0.008). The blinded visual read showed a high level of agreement between all readers (κ = 0.88). Two of 3 readers were in full agreement on all images; 1 reader disagreed on 1 of the 17 NPH cases. Blinded visual assessments of PET images by 1 reader were associated with 100% sensitivity to the overall pathology read, and assessments by the 2 others were associated with 75% sensitivity (overall sensitivity by majority read was 75%); specificity of all readers was 100%. CONCLUSIONS: [(18)F]Flutemetamol detects brain amyloid-ß in vivo and shows promise as a valuable tool to study and possibly facilitate diagnosis of Alzheimer's disease both in patients with suspected NPH and among the wider population.

Clinical utility of dopamine transporter single photon emission CT (DaT-SPECT) with (123I) ioflupane in diagnosis of parkinsonian syndromes.

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 ((123)I)ioflupane (DaTSCAN or DaTscan or ((123)I)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 ((123)I)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 ((123)I)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.

An in vivo evaluation of cerebral cortical amyloid with [18F]flutemetamol using positron emission tomography compared with parietal biopsy samples in living normal pressure hydrocephalus patients.

PURPOSE: The primary objectives of this study were to assess the safety of [(18)F]flutemetamol injection and determine the level of association between the quantitative estimates of brain uptake of [(18)F]flutemetamol and the quantitative immunohistochemical (IHC) estimates of amyloid levels in cerebral cortex biopsies obtained during shunt placement in patients with normal pressure hydrocephalus (NPH). PROCEDURES: Parietal lobe biopsies were obtained from 12 subjects (mean (SD), 71 (8.1) years), during shunt placement for NPH. Shunt procedures and biopsies were performed within 8 weeks after the positron emission tomography (PET) imaging, and followed by a computed tomography scan. The quantitative estimates of the brain uptake of [(18)F]flutemetamol (standard uptake value ratios (SUVRs)) from the biopsy site, contralateral to the biopsy site, and composite were made from the analysis of PET images. The quantitative IHC levels of amyloid load were estimated using a monoclonal antiamyloid ß antibody, 4 G8 (in percent area), as the standard of truth (N = 8, of which 5 had full histopathology staining). The primary analysis determined the level of association between the SUVR (with cerebellum as the reference region) from the biopsy site, and the level of amyloid was determined from IHC estimates of amyloid in the biopsy sample. RESULTS: [(18)F]Flutemetamol injection was found to be well tolerated. The biopsied area well represented the amyloid deposition throughout the cortex in this small sample. The biopsy site SUVR was significantly correlated with the biopsy specimen amyloid ß level (expressed as percent of biopsy specimen area staining with 4 G8). The full model was significant (p = 0.0174). In the secondary efficacy analyses, contralateral (to biopsy site) and composite SUVR values correlated significantly with the percent of biopsy specimen staining for amyloid ß based on 4 G8. Blinded visual [(18)F]flutemetamol image interpretations showed a sensitivity of 100 % and a specificity of 100 % with pathology reads staining for amyloid plaque with Bielschowsky and thioflavin S and overall pathology read. The results of the blinded reader agreement for [(18)F]flutemetamol PET showed full agreement among three readers. CONCLUSIONS: PET imaging of NPH patients following the administration of [(18)F]flutemetamol injection was highly correlated with the presence of fibrillar amyloid ß in subsequent cortical biopsy samples in this small sample. Administration of [(18)F]flutemetamol injection was well tolerated.

Changes in clinical management and diagnosis following DaTscan SPECT imaging in patients with clinically uncertain parkinsonian syndromes: a 12-week follow-up study.

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 [(123)I] 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.

[(18)F]Flutemetamol PET imaging and cortical biopsy histopathology for fibrillar amyloid ß detection in living subjects with normal pressure hydrocephalus: pooled analysis of four studies.

Molecular imaging techniques developed to 'visualize' amyloid in vivo represent a major achievement in Alzheimer's disease (AD) research. This pooled analysis of four studies determined the level of association between uptake of the fibrillar amyloid ß positron emission tomography (PET) imaging agent [(18)F]flutemetamol (Pittsburgh Compound B analog with a 5.5 times longer half-life to enable it to be used in the clinical setting) and neuritic plaques and fibrillar amyloid ß measured by pathologic staining of cortical region biopsy samples. Fifty-two patients with suspected normal pressure hydrocephalus underwent prospective (n = 30) or retrospective (n = 22) [(18)F]flutemetamol PET imaging for detection of cerebral cortical fibrillar amyloid ß and cortical brain biopsy during intracranial pressure measurement or ventriculo-peritoneal shunting. [(18)F]Flutemetamol uptake was quantified using standardized uptake value ratio (SUVR) with cerebellar cortex as the reference region. Tissue fibrillar amyloid ß was evaluated using immunohistochemical monoclonal antibody 4G8 and histochemical agents Thioflavin S and Bielschowsky silver stain, and an overall pathology result based on all available immunohistochemical and histochemical results. Biopsy site and contralateral [(18)F]flutemetamol SUVRs were significantly associated with neuritic plaque burden assessed with Bielschowsky silver stain (r (spearman's) = 0.61, p = 0.0001 for both), as was the composite SUVR with biopsy pathology (r (spearman's) = 0.74, p < 0.0001). SUVR and immunohistochemical results with 4G8 for detecting fibrillar amyloid ß were similar. Blinded image evaluation showed strong agreement between readers (κ = 0.86). Overall sensitivity and specificity by majority read were 93 and 100 %. Noninvasive in vivo [(18)F]flutemetamol PET imaging demonstrates strong concordance with histopathology for brain fibrillar amyloid ß, supporting its promise as a tool to assist physicians with earlier detection of the disease process and making diagnostic decisions about concomitant AD and other diseases associated with brain amyloidosis.