PubMed Health⌕ Search

Biomedical subjects

Kirk A Frey

Publications and source records attributed to Kirk A Frey.

At least 19 recordsLinked to original sources
PubMed2006

Cognitive function and nigrostriatal markers in abstinent methamphetamine abusers.

OBJECTIVE: Preclinical investigations have established that methamphetamine (MA) produces long-term changes in dopamine (DA) neurons in the striatum. Human studies have suggested similar effects and correlated motor and cognitive deficits. The present study was designed to further our understanding of changes in brain function in humans that might result from chronic high dose use of MA after at least 3 months of abstinence. METHOD: Brain function in abstinent users was compared to controls using neuroimaging of monoamine transporters and cognitive assessment. Striatal levels of DA transporter (DAT) and vesicular monoamine transporter type-2 (VMAT2) were determined using [11C]methylphenidate and [11C]dihydrotetrabenazine positron emission tomography, respectively. Cognitive function was evaluated using tests of motor function, memory, learning, attention, and executive function. RESULTS: Striatal DAT was approximately 15% lower and VMAT2 was 10% lower in MA abusers across striatal subregions. The MA abusers performed within the normal range but performed more poorly compared to controls on three of the 12 tasks. CONCLUSIONS: Failure to find more substantial changes in transporter levels and neurocognitive function may be attributed to the length of time that MA users were abstinent (ranging from 3 months to more than 10 years, mean 3 years), although there were no correlations with length of abstinence. Persistent VMAT2 reductions support the animal literature indicating a toxic effect of MA on nigrostriatal nerve terminals. However, the magnitude of the MA effects on nigrostriatal projection integrity is sufficiently small that it is questionable whether clinical signs of DA deficiency are likely to develop.

Adolescent↗
PubMed2006

Positron emission tomography of monoaminergic vesicular binding in aging and Parkinson disease.

The type-2 vesicular monoamine transporter (VMAT2) might serve as an objective biomarker of Parkinson disease (PD) severity. Thirty-one subjects with early-stage PD and 75 normal subjects underwent continuous intravenous infusion of (+)-[(11)C]dihydrotetrabenazine (DTBZ) and positron emission tomography (PET) imaging to estimate the striatal VMAT2 binding site density with equilibrium tracer modeling. Parkinson disease patients were evaluated clinically in the practically defined 'off' state with the Unified Parkinson Disease Rating Scale (UPDRS), the Hoehn and Yahr Scale (HY), and the Schwab and England Activities of Daily Living Scale (SE). In normal subjects there was age-related decline in striatal DTBZ binding, approximating 0.5% per year. In PD subjects, specific DTBZ binding was reduced in the caudate nucleus (CD; -44%), anterior putamen (-68%), and posterior putamen (PP; -77%). The PP-to-CD ratio of binding was reduced significantly in PD subjects. Dihydrotetrabenazine binding was also reduced by approximately 50% in the PD substantia nigra. Striatal binding reductions correlated significantly with PD duration and SE scores, but not with HY stage or with UPDRS motor subscale (UPDRS(III)) scores. Striatal and midbrain DTBZ binding was asymmetric in PD subjects, with greatest reductions contralateral to the most clinically affected limbs. There was significant correlation between asymmetry of DTBZ binding and clinical asymmetry measured with the UPDRS(III). In HY stage 1 and 1.5 subjects (n=16), PP DTBZ binding contralateral to the clinically unaffected body side was reduced by 73%, indicating substantial preclinical nigrostriatal pathology in PD. We conclude that (+)-[(11)C]DTBZ-PET imaging displays many properties necessary of a PD biomarker.

Adult↗
PubMed2006

Lymphatic mapping and sentinel lymph node biopsy for patients with local recurrence after breast-conservation therapy.

BACKGROUND: Local recurrence (LR) after breast-conservation therapy for breast cancer occurs in 10% to 15% of cases. A subset of these represents biologically aggressive disease, yet prognostic features for identifying this high-risk category are lacking. We hypothesized that lymphatic mapping and sentinel lymph node biopsy would provide useful information regarding dominant lymphatic drainage patterns of patients with LR. METHODS: Breast cancer case records involving surgery for LR at the University of Michigan from 2002 to 2004 were reviewed. The lymphatic drainage patterns were compared with those of 117 patients who underwent mapping for primary breast cancer. RESULTS: Fourteen LR cases were identified (10 with initial axillary lymph node dissection, 2 with initial sentinel lymph nodes, and 2 with no axillary surgery at the time of primary cancer treatment); lymphatic mapping was performed in 10. The sentinel lymph node identification rate was 90%, the median number of lymph nodes retrieved was 3, and no metastases were detected. Significantly more cases of nonipsilateral axillary sentinel node drainage were observed in mapping procedures performed for LR compared with those for primary breast cancer (67% vs. 15%; P = .001). CONCLUSIONS: Lymphatic mapping is feasible in patients undergoing mastectomy for LR and is likely to identify aberrantly located sentinel lymph nodes that would otherwise be overlooked with a conventional completion mastectomy.

Adult↗
PubMed2006

In vivo butyrylcholinesterase activity is not increased in Alzheimer's disease synapses.

OBJECTIVE: We tested the premise that cholinesterase inhibitor therapy should target butyrylcholinesterase (BuChE) in Alzheimer's disease (AD), not acetylcholinesterase (AChE) alone, because both enzymes hydrolyze acetylcholine, and BuChE is increased in AD cerebral cortex. METHODS: To examine this issue in vivo, we quantified human cerebral cortical BuChE activity using tracer kinetic estimates (k(3)) of 1-[(11)C]methyl-4-piperidinyl n-butyrate ([(11)C]BMP) hydrolysis determined by positron emission tomography. Validation of the putative positron emission tomography method included regional distribution, positive correlation with age, and attenuation by the nonselective cholinesterase inhibitor physostigmine, but no attenuation by the AChE-selective inhibitor donepezil. Positron emission tomography scans in AD patients (n = 15) and control subjects (n = 12) measured both BuChE (using [(11)C]BMP) and AChE activity (using N-[(11)C] methylpiperidin-4-yl propionate, an established method). RESULTS: As expected, AChE activity in AD cerebral cortex was decreased to 75 +/- 13% of normal (p = 0.00001). Contrary to prediction, accompanying BuChE activity also was decreased to 82 +/- 14% of normal (p = 0.001). INTERPRETATION: Failure to observe increased [(11)C]BMP hydrolysis in vivo makes it less likely that incremental BuChE contributes importantly to acetylcholine hydrolysis in AD. The findings do not support the premise that inhibitor therapy should target BuChE so as to prevent increased levels of BuChE from hydrolyzing acetylcholine in AD cerebral cortex.

Acetylcholinesterase↗
PubMed2006

Patient selection and assessment recommendations for deep brain stimulation in Tourette syndrome.

In response to recent publicity regarding the potential use of deep brain stimulation (DBS) for reducing tic severity in Tourette's syndrome (TS), the Tourette Syndrome Association convened a group of TS and DBS experts to develop recommendations to guide the early use and potential clinical trials of DBS for TS and other tic disorders. The goals of these recommendations are to ensure that all surgical candidates are (1) fully informed about the risks, benefits, and alternative treatments available; (2) receive a comprehensive evaluation before surgery to ensure that DBS is clearly the appropriate clinical treatment choice; and (3) that early clinical experience will be documented publicly to facilitate rational decision-making for both clinical care and future clinical trials.

Deep Brain Stimulation↗
PubMed2006

Neuroimaging of Tourette syndrome.

Traditional neuropathologic methods have provided only limited insight into the central nervous system abnormalities underlying Tourette syndrome. In the past 20 years, investigators have turned increasingly to in vivo neuroimaging approaches to localize, quantify, and characterize neuroanatomic, functional, and neurochemical distinctions in living subjects with Tourette syndrome. Research methods have included aggregate measures of cerebral energy metabolism, assessments of cerebral structure and size, and highly specific assessments of neurochemical markers of select neurons and synapses. Although the available data have important limitations, an encouraging convergence of findings implicates abnormal function in the Tourette syndrome striatum and in associated limbic and frontal cortical systems.

Brain↗
PubMed2005

Hippocampal inactivation disrupts the acquisition and contextual encoding of fear extinction.

In recent studies, inactivation of the dorsal hippocampus before the retrieval of extinguished fear memories disrupted the context-dependent expression of these memories. In the present experiments, we examined the role of the dorsal hippocampus in the acquisition of extinction. After pairing an auditory conditional stimulus (CS) with an aversive footshock [unconditional stimulus (US)], rats received an extinction session in which the CS was presented without the US. In experiment 1, infusion of muscimol, a GABAA receptor agonist, into the dorsal hippocampus before the extinction training session decreased the rate of extinction. Moreover, when later tested for fear to the extinguished CS, all rats that had received hippocampal inactivation before extinction training demonstrated renewed fear regardless of the context in which testing took place. This suggests a role for the dorsal hippocampus in both acquiring the extinction memory and encoding the CS-context relationship that yields the context dependence of extinction. In experiment 2, inactivation of the dorsal hippocampus before testing also disrupted the context dependence of fear to the extinguished CS. In experiment 3, quantitative autoradiography revealed the boundaries of muscimol diffusion after infusion into the dorsal hippocampus. Together, these results reveal that the dorsal hippocampus is involved in the acquisition, contextual encoding, and context-dependent retrieval of fear extinction. Learning and remembering when and where aversive events occur is essential for adaptive emotional regulation.

Acoustic Stimulation↗
PubMed2005

Intratumoral injection of BCNU in ethanol (DTI-015) results in enhanced delivery to tumor--a pharmacokinetic study.

Solvent facilitated perfusion (SFP) has been proposed as a technique to increase the delivery of chemotherapeutic agents to tumors. SFP entails direct injection of the agent into the tumor in a water-miscible organic solvent, and because the solvent moves easily through both aqueous solutions and cellular membranes it drives the penetration of the solubilized anticancer agent throughout the tumor. To test this hypothesis, we compared the pharmacokinetics (PK) of 14C-labeled 1,3-bis-chlorethyl-1-nitrosourea (BCNU) in intra-cerebral 9L rat gliomas after intravenous (IV) infusion in 90% saline--10% ethanol or direct intratumoral (IT) injection of 14C-BCNU in 100% ethanol (DTI-015). Treatment with DTI-015 yielded a peak radioactive count (Cmax) for the 14C label that was 100-1000 fold higher in the tumor than in all other tissues in addition to a concentration in the tumor that was 100-fold higher than that achieved following IV infusion of 14C-BCNU. Pathologic and auto-radiographic analysis of tissue sections following IT injection of 14C-BCNU in ethanol into either tumor or normal rat brain revealed both an enhanced local volume of distribution and an increased concentration of BCNU delivered to tumor compared to non-tumor bearing brain. To investigate the mechanism behind the SFP of BCNU to the tumor both dynamic contrast and perfusion MRI were performed on 9L tumors before and after treatment and demonstrated a decrease in tumor perfusion following IT injection of DTI-015. Finally, initial PK of patient blood samples following administration of DTI-015 into relapsed high-grade glioma indicated a 20-fold decrease in systemic exposure to BCNU compared to IV infusion of BCNU providing further evidence for the enhanced therapeutic ratio observed for DTI-015.

Animals↗
PubMed2005

Dopaminergic abnormalities in select thalamic nuclei in schizophrenia: involvement of the intracellular signal integrating proteins calcyon and spinophilin.

OBJECTIVE: While both thalamic abnormalities and dopaminergic dysregulation have been separately implicated in the pathophysiology of schizophrenia, little is known about the possible dysfunction of molecules associated with dopaminergic neurotransmission in the thalamus in this illness. In this study, the authors studied this question by measuring in postmortem brain the expression of molecules associated with dopaminergic neurotransmission. METHOD: Using in situ hybridization and receptor autoradiography, the authors determined in schizophrenia and comparison subjects 1) thalamic expression of the transcripts encoding the five dopamine receptors; 2) binding to the dopamine D(1), D(2), and D(3) receptors; 3) monoaminergic innervation as assessed by binding to the vesicular monoamine transporter; and 4) transcripts encoding three dopamine receptor-associated intracellular proteins (calcyon, spinophilin, and DARPP-32) that mediate integration of dopaminergic signaling with other neurotransmitter systems. RESULTS: Both calcyon and spinophilin transcripts were significantly elevated in schizophrenia subjects. Monoaminergic innervation, as well as dopamine receptor transcripts and binding sites, were unaffected in this illness. CONCLUSIONS: These data indicate that there are dopaminergic abnormalities in the thalamus in schizophrenia but that they are at the level of intracellular integration of dopamine signaling with other neurotransmitter systems, likely including glutamate, in thalamic neurons.

Aged↗
PubMed2005

11C-DTBZ and 18F-FDG PET measures in differentiating dementias.

UNLABELLED: Accurate, early differentiation of dementias will become increasingly important as new therapies are introduced. Differential diagnosis by standard clinical criteria has limited accuracy. PET offers the potential to increase diagnostic accuracy. (18)F-FDG studies detect metabolic abnormalities in demented patients, but with limited specificity. PET also offers the ability to quantify other biochemical markers that can yield additional useful diagnostic information. We demonstrate that (+)-(11)C-dihydrotetrabenazine ((11)C-DTBZ) studies, which provide an index of nigrostriatal terminal density (distribution volume; DV), also provide a measure of transport (K(1)) that produces information comparable to the metabolic measure of (18)F-FDG. METHODS: Fifty-two patients and 19 control subjects underwent both (11)C-DTBZ and (18)F-FDG PET scans. Seven had the clinical diagnosis of frontotemporal dementia (FTD), 25 had Alzheimer's disease (AD), and 20 had dementia with Lewy bodies (DLB). DTBZ scans provided maps of K(1) and DV, whereas (18)F-FDG scans provided maps of glucose metabolism. Correlation analyses were performed between the different PET measures both within and across subjects. Discriminant analysis using logistic regression compared the performance of (11)C-DTBZ K(1) and (18)F-FDG in differentiating subject groups. Three experienced PET researchers participated in an interrater reliability study using both (11)C-DTBZ K(1) and (18)F-FDG images. RESULTS: Within-subject correspondence between (11)C-DTBZ K(1) and (18)F-FDG measures was high, with correlations averaging 0.92. Correlations between the (11)C-DTBZ DV and either K(1) or (18)F-FDG were far lower, averaging 0.37 and 0.31, respectively, indicating the much higher degree of similarity in information provided by K(1) and (18)F-FDG compared with the very different information provided by (11)C-DTBZ DV. Discriminant analysis demonstrated that (11)C-DTBZ K(1) and (18)F-FDG yielded similar levels of sensitivity and specificity for differentiating the subjects in this study. Including (11)C-DTBZ DV in addition to either K(1) or (18)F-FDG improved discrimination between groups. The raters classified PET scans nearly equivalently using K(1) and (18)F-FDG. CONCLUSION: Multiple PET measures, whether 2 parameters from a single PET study such as (11)C-DTBZ K(1) and DV, or 2 parameters from different studies such as (18)F-FDG and (11)C-DTBZ DV, offer complementary information useful for diagnosing dementias. K(1) and DV images generated from a single (11)C-DTBZ scan provide as much diagnostic information as 2-scan studies using both (11)C-DTBZ and (18)F-FDG.

Aged↗
PubMed2004

Differential effects of scopolamine on in vivo binding of dopamine transporter and vesicular monoamine transporter radioligands in rat brain.

The in vivo equilibrium specific binding of d-threo-[3H]methylphenidate, a radioligand for the dopamine transporter (DAT), and +-alpha-[3H]dihydrotetrabenazine, a radioligand for the vesicular monoamine transporter (VMAT2), were examined in rat brain with and without prior administration of 5 mg/kg scopolamine. Drug-treated animals exhibited a 30% increase in d-threo-[3H]methylphenidate binding to the DAT in the striatum relative to controls. No changes in specific binding of +-alpha-[3H]dihydrotetrabenazine were observed in any brain region following scopolamine pretreatment. Cholinergic drugs thus differentially affect in vivo specific binding of DAT and VMAT2 radioligands, suggesting this should be a consideration in selection of in vivo markers for imaging studies of dopaminergic terminals in the brain of animals and humans.

Animals↗
PubMed2004

Neurochemical imaging of dementias.

Neurochemical imaging is one of the most established "molecular" imaging techniques. There have been tremendous efforts expended to develop radioligands specific to each neurochemical system. Investigational applications of neurochemical imaging in dementing disorders are extensive. Cholinergic, dopaminergic, and serotonergic systems, as well as benzodiazepine receptors, opioid receptors, and glutamatergic receptors have been imaged in Alzheimer disease and other dementing disorders. These investigations have provided important insights into disease processes in living human patients. The clinical diagnostic use of neurochemical imaging for dementing disorders is currently limited, but this technique is used to help develop therapeutic drugs at multiple levels.

Acetylcholine↗
PubMed2003

Initial agonist treatment of Parkinson disease: a critique.

The evidence supporting initial dopamine agonist treatment of PD is reviewed. The two rationales for initial agonist treatment are reduced frequency of motor complications and possible relative neuroprotection by dopamine agonists. The basic science supporting these rationales is equivocal. The clinical evidence for advantages of initial agonist treatment is incomplete. More data are required to determine the optimal initial treatment for PD.

Animals↗
PubMed2003

Diminished striatal [123I]iodobenzovesamicol binding in idiopathic cervical dystonia.

Striatal dysfunction is thought to underlie many dystonias. We used [(123)I]iodobenzovesamicol single-photon emission computed tomography imaging to determine the density of cholinergic terminals in the striatum and other brain regions in 13 subjects with idiopathic cervical dystonia. Striatal [(131)I]iodobenzovesamicol binding was reduced. These results support a role for striatal dysfunction in idiopathic dystonias and suggest diminished striatal cholinergic interneuron density in cervical dystonia.

Adult↗
PubMed2003

Treatment effects on nigrostriatal projection integrity in partial 6-OHDA lesions: comparison of L-DOPA and pramipexole.

There is controversy over potential effects of dopaminergic replacement therapies on the partially lesioned nigrostriatal dopaminergic projection. We evaluated indirect (levodopa, L-DOPA) versus direct (pramipexole, PRA) dopaminergic treatment effects on nigrostriatal lesion severity as measured with vesicular monoamine transporter type-2 (VMAT2) binding. Prior studies have shown that striatal VMAT2 density provides an objective estimate of dopaminergic neuronal integrity, without confounding effects of compensatory regulation. Partial unilateral median forebrain bundle lesions were made by injection of 6-hydroxydopamine in adult male Sprague-Dawley rats. Lesion severity was estimated using rotational behavior after injections of apomorphine and amphetamine. Rats were ranked and matched in pairs by rotation and assigned to receive either PRA (1 mg/kg/day) or L-DOPA/benserazide (100/25 mg/kg/day) ip via osmotic pump. After 4 weeks of drug treatment, in vitro autoradiography was performed with [(3)H]methoxytetrabenazine to measure striatal VMAT2 binding density. Lesion-to-intact VMAT2 density correlated with rotation in both treatment groups. There was no treatment effect on VMAT2 expression in the partially lesioned striatum and thus no differential effect of indirect versus direct dopamimetic treatment on nigrostriatal integrity.

Amphetamine↗
PubMed2003

The role of positron emission tomography imaging in movement disorders.

PET imaging provides the means to study neurochemical, hemodynamic, or metabolic processes that underlie movement disorders in vivo. Because the extent of presynaptic nigrostriatal dopaminergic denervation can be quantified in PD even at an early or preclinical stage of the disease, PET imaging may allow the selection of at-risk subjects for neuroprotective intervention trials. These techniques may also provide markers to follow progression of disease or evaluate the effects of neurorestorative interventions in patients who have more advanced disease. PET is expected to play an increasing role in the selection of patients who have PD for deep brain stimulation. Dopaminergic studies may have a limited clinical role in the diagnosis of patients who have symptoms that suggestive of PD yet do not respond to typical dopaminergic drugs, such as patients who have vascular parkinsonism or ET with mild resting tremor who may have normal dopaminergic innervation. The differential diagnosis between PD and multiple system atrophy, progressive supranuclear palsy, or corticobasal degeneration is not yet clearly established by PET, but combined pre- and postsynaptic dopaminergic imaging may be able to distinguish early idiopathic PD from atypical parkinsonian disorders, in general. Huntington's chorea is characterized by more prominent striatal dopamine receptor loss, whereas nigrostriatal denervation is present to a lesser degree. Patients who have TS may have enhanced synaptic dopamine release in the putamen. Functional imaging studies have generally failed to demonstrate nigrostriatal denervation in essential tremor or idiopathic dystonia. Studies have shown striatal dopamine receptor loss in selected subtypes of dystonic patients. In conclusion, it is expected that PET will help us to better understand the pathophysiology of movement disorders, increase the diagnostic accuracy, allow preclinical diagnosis, monitor disease progression, and evaluate the efficacy of therapeutic agents. Pharmacologic radioligand displacement studies and the development of new nondopaminergic ligands may further aid in the unraveling of cerebral mechanisms that underlie movement disorders.

Brain↗
PubMed2003

Protein synthesis in the amygdala, but not the auditory thalamus, is required for consolidation of Pavlovian fear conditioning in rats.

The amygdala is an essential neural substrate for Pavlovian fear conditioning. Nevertheless, long-term synaptic plasticity in amygdaloid afferents, such as the auditory thalamus, may contribute to the formation of fear memories. We therefore compared the influence of protein synthesis inhibition in the amygdala and the auditory thalamus on the consolidation of Pavlovian fear conditioning in Long-Evans rats. Rats received three tone-footshock trials in a novel conditioning chamber. Immediately after fear conditioning, rats were infused intra-cranially with the protein synthesis inhibitor, anisomycin. Conditional fear to the tone and conditioning context was assessed by measuring freezing behaviour in separate retention tests conducted at least 24 h following conditioning. Post-training infusion of anisomycin into the amygdala impaired conditional freezing to both the auditory and contextual stimuli associated with footshock. In contrast, intra-thalamic infusions of anisomycin or a broad-spectrum protein kinase inhibitor [1-(5'-isoquinolinesulphonyl)-2-methylpiperazine, H7] did not affect conditional freezing during the retention tests. Pre-training intra-thalamic infusion of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (APV), which blocks synaptic transmission in the auditory thalamus, produced a selective deficit in the acquisition of auditory fear conditioning. Autoradiographic assays of cerebral [14C]-leucine incorporation revealed similar levels of protein synthesis inhibition in the amygdala and thalamus following intra-cranial anisomycin infusions. These results reveal that the establishment of long-term fear memories requires protein synthesis in the amygdala, but not the thalamus, after auditory fear conditioning. Forms of synaptic plasticity that depend on protein synthesis, such as long-term potentiation, are likely candidates for the encoding and long-term storage of fear memories in the amygdala.

Amygdala↗