Real Time Imaging of Biomarkers in the Parkinson\u27s Brain Using Mini-Implantable Biosensors. II. Pharmaceutical Therapy with Bromocriptine

We used Neuromolecular Imaging (NMI) and trademarked BRODERICK PROBE® mini-implantable biosensors, to selectively and separately detect neuro-transmitters in vivo, on line, within seconds in the dorsal striatal brain of the Parkinson’s Disease (PD) animal model. We directly compared our results derived from PD to the normal striatal brain of the non-Parkinson’s Disease (non-PD) animal. This advanced biotechnology enabled the imaging of dopamine (DA), serotonin (5-HT), homovanillic acid (HVA) a metabolite of DA, L-tryptophan (L-TP) a precursor to 5-HT and peptides, dynorphin A 1-17 (Dyn A) and somatostatin (somatostatin releasing inhibitory factor) (SRIF). Each neurotransmitter and neurochemical was imaged at a signature electroactive oxidation/half-wave potential in dorsal striatum of the PD as compared with the non-PD animal. Both endogenous and bromocriptine-treated neurochemical profiles in PD and non-PD were imaged using the same experimental paradigm and detection sensitivities. Results showed that we have found significant neurotransmitter peptide biomarkers in the dorsal striatal brain of endogenous and bromocriptine-treated PD animals. The peptide biomarkers were not imaged in dorsal striatal brain of non-PD animals, either endogenously or bromocriptine-treated. These findings provide new pharmacotherapeutic strategies for PD patients. Thus, our findings are highly applicable to the clinical treatment of PD

Oligosaccharides from placenta: early diagnosis of feline mannosidosis

AbstractHigh-pressure liquid chromatography analysis of oligosaccharides from placentas allowed the diagnosis of α-mannosidosis in three litters of kittens. The chromatography also afforded a detailed comparison of the oligosaccharide pattern and levels in placenta, liver, brain, urine and ocular fluid of the affected animals. In all cases, two series of compounds were observed, with one or two residues of N-acetylglucosamine at the reducing terminus, respectively, and between two and nine mannose residues. This pattern is unlike that of human mannosidosis, and resembles that of ruminants, except that the major oligosaccharide contains three mannose residues instead of two

GM2-gangliosidosis B1 variant: analysis of beta-hexosaminidase alpha gene abnormalities in seven patients.

A single nucleotide transition within exon 5 of the beta-hexosaminidase alpha chain gene was identified in a Puerto Rican patient with GM2-gangliosidosis B1 variant as the mutation responsible for the unusual enzymological characteristics of this variant (G533----A; Arg178----His) (the DN-allele). A total of seven patients with enzymological characteristics of B1 variant have since been studied. They were Puerto Rican (DN), Italian, French, Spanish, two patients of mixed ethnic origin (English/Italian/Hungarian and English/French/Azores), and a Czechoslovakian. In confirmation of our earlier finding based on screening with allele-specific probes, all patients except the one from Czechoslovakia carried the same DN-allele. A new point mutation found in this patient changed the same codon affected in the DN-allele (C532----T; Arg178----Cys). An asymptomatic Japanese individual included as a control also carried one allele with the DN-mutation. Site-directed mutagenesis and expression studies in COS I cells demonstrated that either of the two point mutations abolishes the catalytic activity of the alpha subunit. The Spanish patient was homozygous for the DN-allele, but others were all compound heterozygotes. The Puerto Rican patient was a compound heterozygote with the DN-mutation in one allele and with the four-base insertion in exon 11, one of the two mutations found in the classical Ashkenazi Jewish Tay-Sachs disease, in the other allele. Abnormalities of the other allele were not identified in all other compound heterozygous patients. In these patients, the level of mRNA derived from the other allele was variable, ranging from being undetectable to being much lower than normal. This series of studies uncovered a new B1 variant mutation, confirmed our preliminary finding that the DN-allele has a surprisingly wide geographic and ethnic distribution, and pointed out the highly complex nature of the molecular genetics of this rare disorder. They also support our working hypothesis that mutations responsible for the unique enzymological characteristics of the B1 variant should be located in or near exon 5 of the gene and that this region of the enzyme protein is critical for its catalytic function

Lessons from everyday stroke care for clinical research and vice versa: comparison of a comprehensive and a research population of young stroke patients

Peer reviewe

Acute Cerebrovascular Disease in the Young The Stroke in Young Fabry Patients Study

Background and Purpose-Strokes have especially devastating implications if they occur early in life; however, only limited information exists on the characteristics of acute cerebrovascular disease in young adults. Although risk factors and manifestation of atherosclerosis are commonly associated with stroke in the elderly, recent data suggests different causes for stroke in the young. We initiated the prospective, multinational European study Stroke in Young Fabry Patients (sifap) to characterize a cohort of young stroke patients. Methods-Overall, 5023 patients aged 18 to 55 years with the diagnosis of ischemic stroke (3396), hemorrhagic stroke (271), transient ischemic attack (1071) were enrolled in 15 European countries and 47 centers between April 2007 and January 2010 undergoing a detailed, standardized, clinical, laboratory, and radiological protocol. Results-Median age in the overall cohort was 46 years. Definite Fabry disease was diagnosed in 0.5% (95% confidence interval, 0.4%-0.8%; n=27) of all patients; and probable Fabry disease in additional 18 patients. Males dominated the study population (2962/59%) whereas females outnumbered men (65.3%) among the youngest patients (18-24 years). About 80.5% of the patients had a first stroke. Silent infarcts on magnetic resonance imaging were seen in 20% of patients with a first-ever stroke, and in 11.4% of patients with transient ischemic attack and no history of a previous cerebrovascular event. The most common causes of ischemic stroke were large artery atherosclerosis (18.6%) and dissection (9.9%). Conclusions-Definite Fabry disease occurs in 0.5% and probable Fabry disease in further 0.4% of young stroke patients. Silent infarcts, white matter intensities, and classical risk factors were highly prevalent, emphasizing the need for new early preventive strategies

Biosensors for Brain Trauma and Dual Laser Doppler Flowmetry: Enoxaparin Simultaneously Reduces Stroke-Induced Dopamine and Blood Flow while Enhancing Serotonin and Blood Flow in Motor Neurons of Brain, In Vivo

Neuromolecular Imaging (NMI) based on adsorptive electrochemistry, combined with Dual Laser Doppler Flowmetry (LDF) is presented herein to investigate the brain neurochemistry affected by enoxaparin (Lovenox®), an antiplatelet/antithrombotic medication for stroke victims. NMI with miniature biosensors enables neurotransmitter and neuropeptide (NT) imaging; each NT is imaged with a response time in milliseconds. A semiderivative electronic reduction circuit images several NT’s selectively and separately within a response time of minutes. Spatial resolution of NMI biosensors is in the range of nanomicrons and electrochemically-induced current ranges are in pico- and nano-amperes. Simultaneously with NMI, the LDF technology presented herein operates on line by illuminating the living brain, in this example, in dorso-striatal neuroanatomic substrates via a laser sensor with low power laser light containing optical fiber light guides. NMI biotechnology with BRODERICK PROBE® biosensors has a distinct advantage over conventional electrochemical methodologies both in novelty of biosensor formulations and on-line imaging capabilities in the biosensor field. NMI with unique biocompatible biosensors precisely images NT in the body, blood and brain of animals and humans using characteristic experimentally derived half-wave potentials driven by oxidative electron transfer. Enoxaparin is a first line clinical treatment prescribed to halt the progression of acute ischemic stroke (AIS). In the present studies, BRODERICK PROBE® laurate biosensors and LDF laser sensors are placed in dorsal striatum (DStr) dopaminergic motor neurons in basal ganglia of brain in living animals; basal ganglia influence movement disorders such as those correlated with AIS. The purpose of these studies is to understand what is happening in brain neurochemistry and cerebral blood perfusion after causal AIS by middle cerebral artery occlusion in vivo as well as to understand consequent enoxaparin and reperfusion effects actually while enoxaparin is inhibiting blood clots to alleviate AIS symptomatology. This research is directly correlated with the medical and clinical needs of stroke victims. The data are clinically relevant, not only to movement dysfunction but also to the depressive mood that stroke patients often endure. These are the first studies to image brain neurotransmitters while any stroke medications, such as anti-platelet/anti-thrombotic and/or anti-glycoprotein are working in organ systems to alleviate the debilitating consequences of brain trauma and stroke/brain attacks

Leukodystrophies: clinical and genetic aspects.

The leukodystrophies comprise an ever-expanding group of rare central nervous system disorders with defined clinical, pathological, and genetic characteristics. The broader term, leukoencephalopathy, is applied to all brain white matter diseases, whether their molecular cause is known. Magnetic resonance imaging has helped to elucidate new forms of leukodystrophy as well as to permit longitudinal studies of disease progression. The white matter abnormality may appear similar in different forms of leukodystrophy so that in most cases, further studies such as magnetic resonance spectroscopy, tissue biopsies, enzyme studies, and molecular DNA analyses are needed to pinpoint the specific diagnosis. The primary inherited leukoencephalopathies include dysmyelinating, hypomyelinative, and vacuolating forms. Metabolic and vascular causes account for most of the secondary forms, but other inherited syndromes are recognized that have their onset in childhood or adult life and are characterized by distinctive clinical and neuropathologic features. This review discusses some of the mechanisms that have been proposed to explain deficiencies of myelin and the molecular genetic bases underlying these disorders

Head trauma can initiate the onset of adreno-leukodystrophy

X-linked adreno-leukodystrophy and its adult variant, adrenomyeloneuropathy, are caused by mutations in ABCD1 that encodes a peroxisomal membrane protein of unknown physiological significance. In spite of identical mutations, they can have markedly divergent neurological and neuropathologic characteristics. Adreno-leukodystrophy classically presents in normal boys with mild neuropsychiatric features, which progress to frank neurological signs, the vegetative state and death in approximately three years. Adrenomyeloneuropathy typically affects young men with spastic paraparesis and sensory ataxia that can progress over decades. The neuropathologic correlate for adreno-leukodystrophy is severe inflammatory demyelination of posterior cerebral white matter, while a chronic distal axonopathy of spinal cord and peripheral nerve occurs in adrenomyeloneuropathy. Consequently, both modifier genes and environmental factors have been implicated in their pathogeneses. We report five cases of adreno-leukodystrophy whose onsets were initiated by moderate to severe head trauma, two of whom were conversions from adrenomyeloneuropathy. Their clinical courses were rapidly incapacitating, short (i.e., weeks to a few years) and fatal due to marked cerebral inflammatory demyelination. These cases, in concert with several previous reports, indicate that head trauma is one environmental factor that can have a profoundly deleterious effect on those genetically at risk for, or with milder clinical phenotypes of, this disease. Avoidance of potential head trauma and a rapid response to episodes of moderate to severe head trauma in this patient population seem prudent