Assessment of response of brain metastases to radiotherapy by PET imaging of apoptosis with ¹⁸F-ML-10.

Purpose: Early assessment of tumor response to therapy is vital for treatment optimization for the individual cancer patient. Induction of apoptosis is an early and nearly universal effect of anticancer therapies. The purpose of this study was to assess the performance of (18)F-ML-10, a novel PET radiotracer for apoptosis, as a tool for the early detection of response of brain metastases to whole-brain radiation therapy (WBRT).

Patient and caregiver perceptions of the social impact of advanced Parkinson's disease and dyskinesias.

Parkinson's disease (PD) exacts a physical and emotional toll on both patients and family. The aim of this study was to compare patient and caregiver perceptions of the social consequences of basic symptoms of PD and levodopa-induced dyskinesias. Forty patients with PD and dyskinesias and 35 of their caregivers completed a self-report questionnaire on the impact of PD and dyskinesias on their feelings of security and embarrassment and participation in family/social events, and indicated their preference for the "on" (with dyskinesias) or the "off" (without dyskinesias) state.

18F-ML-10, a PET tracer for apoptosis: first human study.

Unlabelled: Clinical PET of apoptosis may have substantial value in advancing patient care. We report here the first-in-humans study with (18)F-labeled 2-(5-fluoropentyl)-2-methyl malonic acid ((18)F-ML-10), a small-molecule PET tracer for apoptosis. Presented are the dosimetry, biodistribution, stability, and safety profiles of this PET tracer in healthy human volunteers.

Residual striatal dopaminergic nerve terminals in very long-standing Parkinson's disease: a single photon emission computed tomography imaging study.

Molecular imaging studies of Parkinson's disease (PD) progression mostly focus on the first 5 years after disease onset, demonstrating rapid initial nigrostriatal neuronal loss. The fate of residual functional dopaminergic nerve terminals in patients with long-standing PD has not yet been specifically explored. Therefore, we performed [(123)I]-FP-CIT single photon emission computed tomography (SPECT) in 15 patients with very long-standing PD (mean disease duration 20.

Small-molecule biomarkers for clinical PET imaging of apoptosis.

Apoptosis is a fundamental biologic process. Molecular imaging of apoptosis in vivo may have important implications for clinical practice, assisting in early detection of disease, monitoring of disease course, assessment of treatment efficacy, or development of new therapies. Although a PET probe for clinical imaging of apoptosis would be highly desirable, this is yet an unachieved goal, mainly because of the required challenging integration of various features, including sensitive and selective detection of the apoptotic cells, clinical aspects such as favorable biodistribution and safety profiles, and compatibility with the radiochemistry and imaging routines of clinical PET centers.

Novel fluorescence molecular imaging of chemotherapy-induced intestinal apoptosis.

Chemotherapy-induced enteropathy (CIE) is one of the most serious complications of anticancer therapy, and tools for its early detection and monitoring are highly needed. We report on a novel fluorescence method for detection of CIE, based on molecular imaging of the related apoptotic process. The method comprises systemic intravenous administration of the ApoSense fluorescent biomarker (N,N(')-didansyl-L-cystine DDC) in vivo and subsequent fluorescence imaging of the intestinal mucosa.

Autoimmune polyendocrine syndrome type I and brain calcinosis.

Autoimmune polyendocrine syndrome (APS) is a rare disorder. One of the possible associated endocrinopathies in APS is hypoparathyroidism. We describe brain calcifications secondary to hypoparathyroidism in family members with APS and compare clinical manifestations, the extent of brain calcifications on CT scans and the result of PET-FDG scans.

Molecular imaging of neurodegeneration by a novel cross-disease biomarker.

Current pre-mortem diagnosis of neurodegenerative disorders such as Alzheimer's disease (AD) or amyotrophic lateral sclerosis (ALS) is based on clinical assessment of neurological deficits. However, symptoms and signs emerge only late in the disease course, thus indicating an urgent need for novel tools for detection of the underlying neuropathology. NST-729 (MW=310) is a novel molecular imaging probe, which is a member of the ApoSense family of small molecule detectors of apoptosis.

Use of a single [123I]-FP-CIT SPECT to predict the severity of clinical symptoms of Parkinson disease.

The aim of this study was to assess the ability of a single SPECT performed in the early stage of Parkinson's disease (PD) to predict disease severity in 19 patients with early PD. [(123)I]-FP-CIT striatal uptake was expressed as a ratio of specific:nonspecific uptake for defined brain areas. Clinical severity was determined by the UPDRS at baseline and 12-15 months following the SPECT procedure.

From the Gla domain to a novel small-molecule detector of apoptosis.

Apoptosis plays a pivotal role in the etiology or pathogenesis of numerous medical disorders, and thus, targeting of apoptotic cells may substantially advance patient care. In our quest for novel low-molecular-weight probes for apoptosis, we focused on the uncommon amino acid gamma-carboxyglutamic acid (Gla), which plays a vital role in the binding of clotting factors to negatively charged phospholipid surfaces. Based on the alkyl-malonic acid motif of Gla, we have developed and now present ML-10 (2-(5-fluoro-pentyl)-2-methyl-malonic acid, MW=206 Da), the prototypical member of a novel family of small-molecule detectors of apoptosis.

Monitoring of tumor response to chemotherapy in vivo by a novel small-molecule detector of apoptosis.

Utilization of molecular imaging of apoptosis for clinical monitoring of tumor response to anti-cancer treatments in vivo is highly desirable. To address this need, we now present ML-9 (butyl-2-methyl-malonic acid; MW = 173), a rationally designed small-molecule detector of apoptosis, based on a novel alkyl-malonate motif. In proof-of-concept studies, induction of apoptosis in tumor cells by various triggers both in vitro and in vivo was associated with marked uptake of (3)H-ML-9 administered in vivo, in correlation with the apoptotic hallmarks of DNA fragmentation, caspase-3 activation and membrane phospholipid scrambling, and with correlative tumor regression.

Molecular imaging of neurovascular cell death in experimental cerebral stroke by PET.

Unlabelled: Clinical molecular imaging of apoptosis is a highly desirable yet unmet challenge. Here we provide the first report on (18)F-labeled 5-fluoropentyl-2-methyl-malonic acid ((18)F-ML-10), a small-molecule, (18)F-labeled PET tracer for the imaging of apoptosis in vivo; this report includes descriptions of the synthesis, radiolabeling, and biodistribution of this novel apoptosis marker. We also describe the use of (18)F-ML-10 for small-animal PET of neurovascular cell death in experimental cerebral stroke in mice.

Targeting cell death in vivo in experimental traumatic brain injury by a novel molecular probe.

Traumatic brain injury (TBI) remains a frequent and major challenge in neurological and neurosurgical practice. Apoptosis may play a role in cerebral tissue damage induced by the traumatic insult, and thus its detection and inhibition may advance patient care. DDC (N,N'-didansyl-L-cystine) is a novel fluorescent probe for detection of apoptotic cells.

Management of motor complications in advanced Parkinson's disease.

After several years of smooth and stable response to levodopa, many patients develop motor fluctuations manifested by "on" and "off" phases. There are various subtypes of motor fluctuations that have different underlying mechanisms and therapeutical strategies. The "wearing off" phenomenon may be mainly due to the loss of stratial dopamine storage capacity and short levodopa half-life.

123I-FP-CIT SPECT imaging of dopamine transporters in patients with recurrent sudden falls: are such falls a distinct entity?

Unlabelled: Recurrent falls in older people are commonly associated with abnormalities that involve several parts of the central nervous system, especially with basal ganglion pathology. The aim of the present study was to evaluate the integrity of striatal dopamine transporters (DaTs) by use of (123)I-N-3-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ((123)I-FP-CIT) SPECT of striatal DaTs in patients with recurrent sudden falls.

Methods: Twenty-one patients without a definite neurologic diagnosis for recurrent sudden falls were enrolled in a cross-sectional study.

Monitoring of chemotherapy-induced cell death in melanoma tumors by N,N'-Didansyl-L-cystine.

Early assessment of the efficacy of anticancer agents is a highly desirable and an unmet need in clinical oncology. Clinical imaging of cell-death may be useful in addressing this need, as induction of tumor cell-death is the primary mechanism of action of most anticancer drugs. In this study, we examined the performance of N,N'-Didansyl-L-cystine (DDC), a member of the ApoSense family of novel small molecule detectors of cell-death, as a potential tool for monitoring cell-death in cancer models.

Novel molecular imaging of cell death in experimental cerebral stroke.

Cell death is the basic neuropathological substrate in cerebral ischemia, and its non-invasive imaging may improve diagnosis and treatment for stroke patients. ApoSense is a novel family of low-molecular weight compounds for detection and imaging of cell death in vivo. We now report on imaging of cell death and monitoring of efficacy of neuroprotective treatment in vivo by intravenous administration of the ApoSense compound DDC (didansylcystine), in experimental stroke in rodents.

Molecular imaging of cell death in vivo by a novel small molecule probe.

Apoptosis has a role in many medical disorders, therefore assessment of apoptosis in vivo can be highly useful for diagnosis, follow-up and evaluation of treatment efficacy. ApoSense is a novel technology, comprising low molecular-weight probes, specifically designed for imaging of cell death in vivo. In the current study we present targeting and imaging of cell death both in vitro and in vivo, utilizing NST-732, a member of the ApoSense family, comprising a fluorophore and a fluorine atom, for both fluorescent and future positron emission tomography (PET) studies using an (18)F label, respectively.

The mystery of motor asymmetry in Parkinson's disease.

The motor symptoms of Parkinson's disease are predominantly due to progressive degeneration of nigral dopaminergic neurons. In most cases there is a substantial asymmetry of clinical symptoms from disease onset, which occurs in sporadic and in hereditary forms of the disease. However, the mechanism of such unilaterality of symptom appearance is not understood.

Effect of dopamine agonists on fatigue and somnolence in Parkinson's disease.

Dopamine agonists are becoming increasingly important in the treatment of early and advanced symptoms of Parkinson disease (PD). Although dopamine agonists are known to increase somnolence, their effect on fatigue and the relationship between fatigue and somnolence have not been investigated thoroughly. The objective of this study is to quantitatively measure fatigue in patients with PD treated with dopamine agonists and to correlate fatigue with somnolence.

ApoSense: a novel technology for functional molecular imaging of cell death in models of acute renal tubular necrosis.

Purpose: Acute renal tubular necrosis (ATN), a common cause of acute renal failure, is a dynamic, rapidly evolving clinical condition associated with apoptotic and necrotic tubular cell death. Its early identification is critical, but current detection methods relying upon clinical assessment, such as kidney biopsy and functional assays, are insufficient. We have developed a family of small molecule compounds, ApoSense, that is capable, upon systemic administration, of selectively targeting and accumulating within apoptotic/necrotic cells and is suitable for attachment of different markers for clinical imaging.

Anti-semaphorin 3A antibodies rescue retinal ganglion cells from cell death following optic nerve axotomy.

Damage to the optic nerve in mammals induces retrograde degeneration and apoptosis of the retinal ganglion cell (RGC) bodies. The mechanisms that mediate the response of the neuronal cells to the axonal injury are still unknown. We have previously shown that semaphorins, axon guidance molecules with repulsive cues, are capable of mediating apoptosis in cultured neuronal cells (Shirvan, A.