Change in PDE10 across early Huntington disease assessed by [18F]MNI-659 and PET imaging.

OBJECTIVE: To evaluate whether striatal [(18)F]MNI-659 PET imaging of phosphodiesterase 10A (PDE10) serves as a sensitive and reliable biomarker of striatal neurodegeneration in a longitudinal cohort of participants with early Huntington disease (HD). METHODS: A cohort of participants with HD, including both participants premanifest or manifest with motor signs, underwent clinical assessments, genetic determination, and 2 [(18)F]MNI-659 PET imaging sessions approximately 1 year apart. Eleven healthy control (HC) participants underwent clinical assessments and [(18)F]MNI-659 PET imaging once. Striatal binding potentials (BPnd) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between baseline and follow-up imaging. Clinical measures of HD severity were assessed at each visit. RESULTS: Eight participants with HD (6 manifest; 2 premanifest) participated. Of those with manifest HD, all had relatively early stage disease (stage 1, n = 2; stage 2, n = 4) and a Unified Huntington's Disease Rating Scale total motor score <45. As expected, the HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of that seen in HC. On follow-up scans, [(18)F]MNI-659 uptake declined in the putamen and caudate nucleus in all 8 participants. The mean annualized rates of decline in signal in the caudate, putamen, and globus pallidus and the putamen were 16.6%, 6.9%, and 5.8%, respectively. In HC, the annualized reduction in signal in striatal regions was less than 1%. CONCLUSION: Longitudinal data in this small cohort of participants with early HD support [(18)F]MNI-659 PET imaging of PDE10 as a useful biomarker to track HD disease progression.

The phosphodiesterase 10 positron emission tomography tracer, [18F]MNI-659, as a novel biomarker for early Huntington disease.

IMPORTANCE: In Huntington disease (HD) striatal neuron loss precedes and predicts motor signs or symptoms. Current imaging biomarkers lack adequate sensitivity for assessing the early stages of HD. Developing an imaging biomarker for HD spanning the time of onset of motor signs remains a major unmet research need. Intracellular proteins whose expression is altered by the mutant huntingtin protein may be superior markers for early HD stages. OBJECTIVE: To evaluate whether [18F]MNI-659 (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), a novel phosphodiesterase 10 positron emission tomography (PET) ligand, is a sensitive marker for striatal changes in early HD. DESIGN, SETTING, AND PARTICIPANTS: A cohort of individuals with HD, including premanifest (pre-HD) or manifest with motor signs (mHD), underwent clinical assessments, genetic determination, [18F]MNI-659 PET imaging, and brain magnetic resonance imaging. Age-matched healthy volunteers (HVs) also received clinical assessments and PET and magnetic resonance imaging. MAIN OUTCOMES AND MEASURES: Binding potentials (BPnds) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between participants with HD and the HVs and correlated with markers of HD severity and atrophy of basal ganglia nuclei. RESULTS: Eleven participants with HD (8 mHD and 3 pre-HD) and 9 HVs participated. Ten of 11 HD participants had known huntingtin CAG repeat length, allowing determination of a burden of pathology (BOP) score. One individual with HD declined CAG determination. All participants with mHD had relatively early-stage disease (4 with stage 1 and 4 with stage 2) and a Unified Huntington's Disease Rating Scale (UHDRS) total Motor subscale score of less than 50. The HD cohort had significantly lower striatal [18F]MNI-659 uptake than did the HV cohort (mean, -48.4%; P < .001). The HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of the level in the HVs (mean, -47.6%; P < .001). The 3 pre-HD participants had intermediate basal ganglia BPnds. Striatal [18F]MNI-659 uptake correlated strongly with the severity of disease measured by the clinical scale (UHDRS Motor subscale; R = 0.903; P < .001), the molecular marker (BOP; R = 0.908; P < .001), and regional atrophy (R = 0.667; P < .05). CONCLUSIONS AND RELEVANCE: As a promising striatal imaging biomarker, [18F]MNI-659 is potentially capable of assessing the extent of disease in early mHD. Furthermore, [18F]MNI-659 may identify early changes in medium spiny neurons and serve as a marker to predict conversion to mHD. Additional studies with larger, stratified cohorts of patients with HD and prospective studies of individuals with pre-HD are warranted.

Performance characteristics of amyloid PET with florbetapir F 18 in patients with alzheimer's disease and cognitively normal subjects.

UNLABELLED: The objectives of this study were to examine the effective dose range and the test-retest reliability of florbetapir F 18 using, first, visual assessment by independent raters masked to clinical information and, second, semiautomated quantitative measures of cortical target area to cerebellum standardized uptake value ratios (SUVr) as primary outcome measures. Visual ratings of PET image quality and tracer retention or ß-amyloid (Aß) binding expressed as SUVrs were compared after intravenous administration of either 111 MBq (3 mCi) or 370 MBq (10 mCi) of florbetapir F 18 in patients with Alzheimer's disease (AD) (n = 9) and younger healthy controls (YHCs) (n = 11). In a separate set of subjects (AD, n = 10; YHCs, n = 10), test-retest reliability was evaluated by comparing intrasubject visual read ratings and SUVrs for 2 PET images acquired within 4 wk of each other. RESULTS: There were no meaningful differences between the 111-MBq (3-mCi) and 370-MBq (10-mCi) dose in the visual rating or SUVr. The difference in the visual quality across 111 and 370 MBq showed a trend toward lower image quality, but no statistical significance was achieved (t test; t(1) = -1.617, P = 0.12) in this relatively small sample of subjects. At both dose levels, visual ratings of amyloid burden identified 100% of AD subjects as Aß-positive and 100% of YHCs as Aß-negative. Mean intrasubject test-retest variability for cortical average SUVrs with the cerebellum as a reference over the 50- to 70-min period was 2.4% ± 1.41% for AD subjects and 1.5% ± 0.84% for controls. The overall SUVr test-retest correlation coefficient was 0.99. The overall κ-statistic for test-retest agreement for Aß classification of the masked reads was 0.89 (95% confidence interval, 0.69-1.0). CONCLUSION: Florbetapir F 18 appears to have a wide effective dose range and a high test-retest reliability for both quantitative (SUVr) values and visual assessment of the ligand. These imaging performance properties provide important technical information on the use of florbetapir F 18 and PET to detect cerebral amyloid aggregates.

Estimating the half-lives of PCB congeners in former capacitor workers measured over a 28-year interval.

To date, most estimates of the half-life of polychlorinated biphenyls (PCBs) in humans have been based on relatively short follow-up periods. To address this issue, we determined the half-lives of PCB congeners of occupational origin in the serum of former capacitor workers as part of a study conducted in 2003-2006--approximately 28 years after their last occupational exposure. A total of 241 persons from a source population of 6798 former capacitor workers were interviewed and asked to donate a blood sample for serum PCB congener analysis. A subgroup of 45 participants also had serum archived from 1976 and reanalyzed for the same 27 PCB congeners by the same laboratory. Our estimates of the half-lives of the congeners among these 45 persons were longer than those reported by Wolff et al. (1992), due primarily to the much longer interval between exposure and determination of serum PCB concentrations. Half-lives were significantly greater for the heavy versus light occupational congeners, for women versus men and for those with low versus high initial exposure. Current serum total PCB concentrations, expressed as the geometric mean of wet weight data, averaged 6.7 ng/g for the entire 241-person cohort, which represents a 10-fold decrease from values reported in the late 1970s, but is still nearly twice the average for persons of similar age residing in the same area, but without occupational exposure. In addition, current serum PCB concentrations remained significantly and positively associated with earlier occupational exposure, but were not associated with fresh water fish consumption. In general, the results support a consistent and long-duration trend of increased PCB body burden in this cohort of former capacitor workers compared with non-occupationally exposed individuals. The results may aid in further understanding the toxicological/epidemiological consequences of exposure to PCBs in humans.

Occupational exposure to PCBs reduces striatal dopamine transporter densities only in women: a beta-CIT imaging study.

We hypothesize that occupational exposure to PCBs is associated with a reduction in central dopamine (DA) similar to changes previously seen in PCB exposed adult non-human primates. To test that hypothesis, we used [(123)I]beta-CIT SPECT imaging to estimate basal ganglia DA transporter density in former capacitor workers. Women, but not men, showed an inverse relationship between lipid-adjusted total serum PCB concentrations and DA transporter densities in the absence of differences in serum PCB concentrations. These sex differences may reflect age-related reductions in the levels of gonadal hormones since these hormones have been shown experimentally to alter response to DA neurotoxicants. These findings may aid in better understanding the roles that sex and age play in modifying central DA function following exposure, not only to PCBs, but also to other DA neurotoxicants as well as further elucidating the role of gonadal hormones in influencing the initiation and/or progression of neurodegenerative disorders.

(123I) beta-CIT and single-photon emission computed tomographic imaging vs clinical evaluation in Parkinsonian syndrome: unmasking an early diagnosis.

BACKGROUND: The diagnosis of Parkinson disease is currently based on clinical evaluation. Functional neuroimaging using (123I) beta-carboxymethyoxy-3-beta-(4-iodophenyl) tropane (CIT) and single-photon emission computed tomography (SPECT) provides information on the integrity of the dopaminergic system in vivo and is a promising diagnostic tool in early Parkinson disease. OBJECTIVE: To evaluate the diagnostic accuracy of dopamine transporter imaging using (123I)beta-CIT in patients with suspected parkinsonian syndrome (PS). DESIGN: Community neurologists referred patients with suspected PS for imaging evaluation. Clinical diagnoses (positive PS or negative PS) were provided by the community neurologists and 2 movement disorder experts. We performed (123I)beta-CIT and SPECT imaging, and imaging diagnoses of positive PS or negative PS were assigned. A 6-month follow-up clinical diagnosis was assigned by a movement disorder expert blind to the imaging data, which represented the "gold standard" diagnosis for the study. RESULTS: Thirty-five patients with suspected PS were referred. Diagnoses in question included essential tremor, psychogenic parkinsonism, drug-induced parkinsonism, primary dystonia, and unspecified gait disorder. Comparing the community neurologist's diagnoses at referral with the gold standard diagnosis, there was dis agreement in 25.7% (sensitivity, 0.92; specificity, 0.30). Comparing the quantitative imaging diagnoses with the gold standard, there was disagreement in 8.6% (sensitivity, 0.92; specificity, 1.00). CONCLUSION: Performing (123I)beta-CIT and SPECT imaging at baseline appears to be a useful diagnostic tool to detect patients thought to have PS at baseline but who, after follow-up, do not have PS.

The natural history of the syndrome of primary progressive freezing gait.

BACKGROUND: Primary progressive freezing gait disorder is considered to be a distinct clinical entity that manifests predominantly as a progressive freezing gait disorder without accompanying abnormalities. However, confusion remains about its clinical presentation, natural history, and classification. OBJECTIVE: To examine the natural history, clinical and brain imaging characteristics, and response to dopaminergic medications of primary progressive freezing gait (PPFG) disorder. DESIGN/METHODS: Review of medical records, videotape examinations, and computed tomographic and magnetic resonance imaging of the brain and results of neurological evaluations, including the Unified Parkinson's Disease Rating Scale, in patients with PPFG. RESULTS: Thirty patients (16 male) were diagnosed as having PPFG (mean age at onset, 72.2 years; mean duration of disease, 5 years). Gait disorder was the initial complaint in 27 patients. Freezing gait was the initial manifestation in 18 and was present within the first year in 27. Natural history included 25 patients falling within 3 years of onset, 20 experiencing retropulsion within 4 years, and 16 requiring wheelchairs by 5 years. On neurological examination, bradykinesia was present in 29 patients, muscle rigidity in 15, and postural tremor in 11. Other features included speech abnormalities in 10, hyperreflexia without clonus in 17, and dementia in 8. Extraocular movement abnormalities and dysphagia were rare. All 30 patients were treated with levodopa with minimal effect. Eighteen were treated with a dopamine agonist with no notable effect. Of the 23 patients with magnetic resonance imaging scans, results were normal in 9 and included minor nonspecific changes in 14. The computed tomographic scans obtained in 12 patients showed similar results. One patient underwent fluorine F ((18)F) labeled deoxyglucose positron emission tomography, which showed mild reduction in medial frontal glucose metabolism. CONCLUSIONS: Primary progressive freezing gait appears to be a clinically distinct progressive neurological disorder that primarily affects gait, initially resulting in freezing and later in postural instability. A wheelchair-bound state often develops within 5 years. It is accompanied by other parkinsonian features, particularly bradykinesia, but is unresponsive to dopaminergic medications. It progresses in a fairly stereotyped manner. Primary progressive freezing gait disorder should be a unifying term for this disorder that has gone by many names in the literature and should be classified as a Parkinson-plus disorder.