Biomedical subjects
R L Albin
Publications and source records attributed to R L Albin.
Vesicular neurotransmitter transporters in Huntington's disease: initial observations and comparison with traditional synaptic markers.
Markers of identified neuronal populations have previously suggested selective degeneration of projection neurons in Huntington's disease (HD) striatum. Interpretations are, however, limited by effects of compensatory regulation and atrophy. Studies of the vesicular monoamine transporter type-2 (VMAT2) and of the vesicular acetylcholine transporter (VAChT) in experimental animals indicate that they are robust markers of presynaptic integrity and are not subject to regulation. We measured dopamine and acetylcholine vesicular transporters to characterize the selectivity of degeneration in HD striatum. Brains were obtained at autopsy from four HD patients and five controls. Autoradiography was used to quantify radioligand binding to VMAT2, VAChT, the dopamine plasmalemmal transporter (DAT), benzodiazepine (BZ) binding sites, and D2-type dopamine receptors. The activity of choline acetyltransferase (ChAT) was determined as an additional marker of cholinergic neurons. Autoradiograms were analyzed by video-assisted densitometry and assessment of atrophy was made from regional structural areas in the coronal projection. Striatal VMAT2, DAT, and VAChT concentrations were unchanged or increased, while D2 and BZ binding and ChAT activity were decreased in HD. After atrophy correction, all striatal binding sites were decreased. However, the decrease in ChAT activity was 3-fold greater than that of VAChT binding. In addition to degeneration of striatal projection neurons, there are losses of extrinsic nigrostriatal projections and of striatal cholinergic interneurons in HD on the basis of vesicular transporter measures. There is also markedly reduced expression of ChAT by surviving cholinergic striatal interneurons.
Neurological abnormalities in a knock-in mouse model of Huntington's disease.
Mice representing precise genetic replicas of Huntington's disease (HD) were made using gene targeting to replace the short CAG repeat of the mouse Huntington's disease gene homolog (HDH:) with CAG repeats within the length range found to cause HD in humans. Mice with alleles of approximately 150 units in length exhibit late-onset behavioral and neuroanatomic abnormalities consistent with HD. These symptoms include a motor task deficit, gait abnormalities, reactive gliosis and the formation of neuronal intranuclear inclusions predominating in the striatum. This model differs from previously described HDH: knock-ins by its method of construction, longer repeat length and more severe phenotype. To our knowledge, this is the first knock-in mouse model of HD to show increased glial fibrillary acidic protein immunoreactivity in the striatum, suggesting that these mice have neuronal injury similar to that found early in the course of HD. These mice will serve as useful reagents in experiments designed to reveal the molecular nature of neuronal dysfunction underlying HD.
Alzheimer's disease versus dementia with Lewy bodies: cerebral metabolic distinction with autopsy confirmation.
Seeking antemortem markers to distinguish Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we examined brain glucose metabolism of DLB and AD. Eleven DLB patients (7 Lewy body variant of AD [LBVAD] and 4 pure diffuse Lewy body disease [DLBD]) who had antemortem position emission tomography imaging and autopsy confirmation were compared to 10 autopsy-confirmed pure AD patients. In addition, 53 patients with clinically-diagnosed probable AD, 13 of whom later fulfilled clinical diagnoses of DLB, were examined. Autopsy-confirmed AD and DLB patients showed significant metabolic reductions involving parietotemporal association, posterior cingulate, and frontal association cortices. Only DLB patients showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex (LBVAD -23% and DLBD -29% vs AD -8%), which distinguished DLB versus AD with 90% sensitivity and 80% specificity. Multivariate analysis revealed that occipital metabolic changes in DLB were independent from those in the adjacent parietotemporal cortices. Analysis of clinically diagnosed probable AD patients showed a significantly higher frequency of primary visual metabolic reduction among patients who fulfilled later dinical criteria for DLB. In these patients, occipital hypometabolism preceded some clinical features of DLB. Occipital hypometabolism is a potential antemortem marker to distinguish DLB versus AD.
Decreased striatal dopaminergic innervation in REM sleep behavior disorder.
REM sleep behavior disorder (RBD) is a possible herald of neurodegenerative disorders with parkinsonism. The authors determined the density of striatal dopaminergic terminals with [11C]dihydrotetrabenazine PET in six elderly subjects with chronic idiopathic RBD and 19 age-appropriate controls. In subjects with RBD, there were significant reductions in striatal [11C]dihydrotetrabenazine binding, particularly in the posterior putamen.
Decreased striatal monoaminergic terminals in Huntington disease.
OBJECTIVE: To evaluate the integrity of the dorsal striatal dopaminergic innervation in rigid and choreic Huntington disease (HD). BACKGROUND: Some patients with HD have an akinetic-rigid phenotype. It has been suggested that nigrostriatal in addition to striatal pathology is present in this subgroup. The authors sought to determine whether in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding could distinguish patients with akinetic-rigid (HDr) from typical choreiform (HDc) HD. METHODS: Nineteen patients with HD (mean age 48 +/- 16 years) and 64 normal controls (mean age 50 +/- 14 years) underwent (+)-alpha-[11C]dihydrotetrabenazine (DTBZ) PET imaging. DTBZ blood to brain ligand transport (K1) and tissue to plasma distribution volume (DV) in the caudate nucleus, anterior putamen, and posterior putamen were normalized to the occipital cortex. RESULTS: The normalized striatal specific DV was reduced in HDr (n = 6) when compared with controls: caudate nucleus -33% (p < 0.001), anterior putamen -56% (p < 0.0001), and posterior putamen -75% (p < 0.0001). Patients with HDc (n = 13) also had reduced striatal DV: caudate nucleus -6% (NS), anterior putamen -19% (p < 0.01), and posterior putamen -35% (p < 0.0001). Patients with HDr had significantly lower striatal (+)-alpha-[11C]DTBZ binding than HDc patients. After correction for tissue atrophy effects, normalized DV differences were less significant, with values somewhat increased in the caudate, slightly reduced in the anterior putamen, and moderately decreased in the posterior putamen. There were no significant regional differences in K1 reductions among caudate, anterior, and posterior putamen in HD. CONCLUSIONS: Reduced striatal VMAT2 binding suggests nigrostriatal pathology in HD, most severely in the HDr phenotype. Striatal DV reductions were most prominent in the posterior putamen, similar to PD.
Increased response to intrastriatal L(+)-2-amino-4-phosphonobutyrate (L-AP4) in unilateral 6-hydroxydopamine-lesioned rats.
Unilateral intrastriatal injection of the prototype Group III metabotropic glutamate receptor agonist L(+)-2-amino-4-phosphonobutyrate (L-AP4) induces rotation in rats with ipsilateral unilateral 6-hydroxydopamine lesions of the nigrostriatal projection but not in unlesioned control animals [Kearney et al., (1998) Neuroscience 87:881-891]. We studied differences in striatal neuron Fos-like immunoreactivity expression, striatal neuron Fos-like immunoreactivity localization, and regional [(14)C]-2-deoxyglucose uptake after unilateral intrastriatal injection of L-AP4 between control and unilateral 6-hydroxydopamine lesioned rats. There was a left shift of the dose response curve with more striatal neurons expressing Fos-like immunoreactivity at lower doses of L-AP4 in 6-hydroxydopamine lesioned animals. In unlesioned striata, L-AP4 injections tended to induce Fos-like immunoreactivity in striato-pallidal projection neurons. In lesioned animals, the majority of striatal neurons expressing Fos-like immunoreactivity were striatonigral projection neurons. In both control and lesioned animals, intrastriatal injection of L-AP4 produced widespread decreases in [(14)C]-2-deoxyglucose uptake in basal ganglia nuclei and related regions, but the magnitude of this effect increased markedly in lesioned animals. Striatal dopamine denervation enhances the response of striatal neurons to intrastriatally injected L-AP4 with an apparent shift in the type of striatal projection neuron responding to L-AP4.
Intrasubthalamic nucleus metabotropic glutamate receptor activation: a behavioral, Fos immunohistochemical and [14C]2-deoxyglucose autoradiographic study.
Metabotropic glutamate receptors are a major class of excitatory amino acid receptors. Eight metabotropic glutamate receptor subtypes have been cloned, and are classified into three groups (I, II and III) based on amino acid sequence identity, effector systems and pharmacological profile. Previous results have shown that unilateral stimulation of metabotropic glutamate receptors in the subthalamic nucleus with the non-subtype-selective metabotropic glutamate receptor agonist 1S,3R-1-amino-1,3-cyclopentane dicarboxylate results in contralateral rotation in rats and Fos expression in the subthalamic nucleus. This suggests that metabotropic glutamate receptor stimulation results in altered subthalamic nucleus activity with consequent altered basal ganglia activity on the injected side. We sought to determine the metabotropic glutamate receptor subtype(s) involved and the functional neuroanatomy underlying the rotational behavior. Unilateral intrasubthalamic nucleus injection of group II or group III metabotropic glutamate receptor agonists induced contralateral rotation. In addition to producing rotation, group II and group III metabotropic glutamate receptor agonists induce toxicity in the subthalamic nucleus and overlying thalamus. Following group II or group III subthalamic nucleus metabotropic glutamate receptor stimulation, there is Fos-like immunoreactivity in the globus pallidus, subthalamic nucleus, substantia nigra pars reticulata and entopeduncular nucleus, suggesting altered activity in subthalamic nucleus target regions. However, examination of [14C]2-deoxyglucose uptake suggests that the alterations in basal ganglia activity are different following group II versus group III metabotropic glutamate receptor stimulation, suggesting that rotation is occurring via different mechanisms. It appears that stimulation of subthalamic nucleus group II metabotropic glutamate receptors induces rotation by increasing subthalamic nucleus activity. These results suggest that group II metabotropic glutamate receptor antagonists may be useful for alleviating subthalamic nucleus overactivity in Parkinson's disease.
Basal ganglia neurotoxins.
The epidemiology, clinical features, pathology, and mechanisms of action of basal ganglia neurotoxins are reviewed. Manganese, cyanide, hydrogen sulfide, methanol, carbon monoxide, 3-nitropropionic acid, MPTP, and annonaceae alkaloids are discussed. The probable mechanism of action for almost all basal ganglia neurotoxins is inhibition of mitochondrial function with destruction of the pallidum and putamen. MPTP produces selective loss of dopaminergic neurons because of selective uptake of a toxic metabolite in dopaminergic neurons. The basis for selective vulnerability of the putamen and pallidum is unknown.
Parkinsonism after correction of hyponatremia with radiological central pontine myelinolysis and changes in the basal ganglia.
Parkinsonism has been rarely described following central pontine and extrapontine myelinolysis. We report a case of parkinsonism developing following rapid correction of hyponatremia with radiological evidence of central pontine myelinolysis and changes in the basal ganglia. A 56-year-old man developed drooling and bilateral hand tremors 3 weeks after correction of hyponatremia from 103 to 125 mmol/L over 14 h. He had a prominent 6 Hz resting tremor which worsened with action and mild cogwheel rigidity. Magnetic resonance imaging (MRI) showed changes consistent with central pontine myelinolysis and increased signal on T1-weighted images in the putamen bilaterally. His tremor responded well to L-dopa therapy. There have been several other cases of parkinsonism developing after central pontine/extrapontine myelinolysis. Increased signal in the basal ganglia on T1-weighted images has been described in another case of central pontine myelinolysis imaged about the same time after sodium correction as our case.
Striatal presynaptic monoaminergic vesicles are not increased in Tourette's syndrome.
BACKGROUND: Abnormal function of striatal dopaminergic synapses is suggested to underlie Tourette's syndrome (TS). OBJECTIVE: To determine dorsal striatal dopaminergic innervation in TS. Prior in vitro and in vivo studies of dopamine reuptake transporter binding sites suggest increased striatal dopaminergic innervation in TS. METHODS: We used in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding to quantify striatal dopaminergic innervation in TS. Eight TS patients (mean age 30+/-9 years) and 22 age-comparable normal controls (age 34+/-8 years) underwent PET imaging with the VMAT2 ligand (+)-alpha-[11C]dihydrotetrabenazine (DTBZ). Compartmental modeling was used to quantify blood-to-brain ligand transport and VMAT2 binding site density from the tissue-to-plasma distribution volume (DV) during continuous (+)-alpha-[11C]DTBZ infusion. DTBZ DV in dorsal striatal regions was expressed relative to the occipital cortex to estimate relative specific VMAT2 binding (binding potential). RESULTS: We found no significant differences in VMAT2 binding potential between patients and controls in the caudate nucleus, anterior putamen, or posterior putamen. There were no significant differences in striatal VMAT2 binding between patients with (n = 5) or without (n = 3) features of obsessive-compulsive disorder. CONCLUSIONS: There is no evidence for increased binding to the VMAT2 in TS striatum and that dorsal striatal dopaminergic innervation density is normal in TS. The previously reported changes in dopamine transporter binding sites may reflect medication effect and/or altered synaptic activity or regulation of dopamine transporter expression in nigrostriatal neurons.
(+)-alpha-[11C]Dihydrotetrabenazine PET imaging in familial paroxysmal dystonic choreoathetosis.
Clinical observations suggest a disturbance of striatal dopaminergic function in familial paroxysmal dystonic choreoathetosis (PDC). The authors used PET with [11C]dihydrotetrabenazine (DTBZ) to study striatal dopaminergic innervation in PDC. The results did not reveal abnormal DTBZ binding potential in PDC striatum. This suggests that dopaminergic abnormalities, if present, may be due to altered regulation of dopamine release or to postsynaptic mechanisms, rather than to an altered density of nigrostriatal innervation.
Time-course analysis and comparison of acute and chronic intrastriatal quinolinic acid administration on forelimb reaching deficits in the rat.
Rats were trained to use a single forelimb for a food pellet retrieval task. During baseline testing all rats exhibited > 90% use of a preferred limb for the task. Following baseline, rats were subjected to chronic administration (18 day) or acute injection of quinolinic acid (QUIN) or vehicle to the striatum contralateral to the preferred limb. Rats were tested 48 h after insertion of chronic delivery probes or after acute injection and retested every 48 h over an 18-day period. Compared to vehicle, rats receiving chronic QUIN (7.6 nmol/h) exhibited an increase in the number of reach attempts required to meet task criteria. Chronic QUIN did not produce a significant change in latency to initiate the task or an increase in latency to complete the task. No rats exposed to chronic QUIN exhibited a switch in limb preference for the task. Unlike animals exposed to chronic QUIN, a significant number of animals receiving acute QUIN injections switched to exclusive use of the ipsilateral (nonpreferred) limb for the task. Quantitative histological analysis revealed no significant difference in lesion volume between acute and chronic lesion animals. These findings suggest that behavioral manifestations of histopathologically similar lesions may be vastly different depending on the methods used to produce these lesions. More specifically, the acute injection model resulted primarily in forelimb disuse, whereas the chronic model resulted in continued abnormal use of the affected limb. Understanding adaptive strategies used in these models may be particularly important when testing newly developed transgenic models of neurodegenerative diseases and the therapeutic potential of newly developed neuroprotectants.
Dystonia associated with mutation of the neuronal sodium channel Scn8a and identification of the modifier locus Scnm1 on mouse chromosome 3.
The mouse mutant medJ contains a splice site mutation in the neuronal sodium channel Scn8a that results in a very low level of expression. On a C57BL/6J genetic background, medJ homozygotes exhibit progressive paralysis and juvenile lethality. The C3H genetic background has an ameliorating effect, producing viable adults with a novel dystonic phenotype. The dystonic mice exhibit movement-induced, sustained abnormal postures of the trunk and limbs. A dominant modifier locus responsible for the difference between strains was mapped to a 4.5 +/- 1.3 cM interval on mouse chromosome 3. Our findings establish a role for ion channels in dystonia and demonstrate the impact of genetic background on its severity and progression. This new model suggests that SCN8A on chromosome 12q13 and SCNM1 on chromosome 1p21-1q21 may contribute to human inherited dystonia.
Muscarinic receptor loss and preservation of presynaptic cholinergic terminals in hippocampal sclerosis.
PURPOSE: Prior single-photon emission tomography studies showed losses of muscarinic acetylcholine receptor (MAChR) binding in patients with refractory mesial temporal lobe epilepsy. Experimental animal studies demonstrated transient losses of MAChR due to electrically induced seizures originating in the amygdala. However, the relations between cholinergic synaptic markers, seizures, and underlying neuropathology in human temporal lobe epilepsy are unknown. We tested the hypotheses that human brain MAChR changes are attributable to hippocampal sclerosis (HS), and that HS resembles axon-sparing lesions in experimental animal models. METHODS: We measured MAChR binding-site density, an intrinsic neuronal marker, within the hippocampal formation (HF) in anterior temporal lobectomy specimens from 10 patients with HS and in 10 autopsy controls. Binding-site density of the presynaptic vesicular acetylcholine transporter (VAChT) was measured as a marker of extrinsic cholinergic afferent integrity. MAChR and VAChT results were compared with neuronal cell counts to assess their relations to local neuronal losses. RESULTS: Reduced MAChR binding-site density was demonstrated throughout the HF in the epilepsy specimens compared with autopsy controls and correlated in severity with reductions in cell counts in several HF regions. In contrast to MAChR, VAChT binding-site density was unchanged in the epilepsy specimens compared with autopsy controls. CONCLUSIONS: Reduction in MAChR binding in HS is attributable to intrinsic neuronal losses. Sparing of afferent septal cholinergic terminals is consistent with the hypothesis that an excitotoxic mechanism may contribute to the development of HS and refractory partial epilepsy in humans.
Absence of mutation in the beta- and gamma-synuclein genes in familial autosomal dominant Parkinson's disease.
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Localization of mGluR1a-like immunoreactivity and mGluR5-like immunoreactivity in identified populations of striatal neurons.
Metabotropic glutamate receptors are important mediators of excitatory amino acid neurotransmission in the striatum. Two-color immunofluorescence histochemistry and immunohistochemistry in combination with retrograde tract-tracing techniques were used to examine the distribution of metabotropic glutamate receptor subtypes 1a and 5 (mGluR1a and mGluR5) among identified subpopulations of striatal projection neurons and interneurons. The majority of striatopallidal and striatonigral neurons were double-labeled for both mGluR1a or mGluR5. Approximately 60% to 70% of either striatonigral or striatopallidal neurons expressed mGluR1a- or mGluR5-like immunoreactivity. The percentage of double-labeled striatopallidal or striatonigral projection neurons did not differ among striatal quadrants. Striatal interneurons expressing parvalbumin or somatostatin or choline acetyltransferase exhibited varying degrees of expression of mGluR1a or mGluR5. Virtually all (94%) parvalbumin-immunoreactive striatal neurons expressed mGluR1a-like immunoreactivity with a majority (79%) of these neurons expressing mGluR5-like immunoreactivity. A high percentage (89%) of striatal choline acetyltransferase-immunoreactive neurons were double-labeled for mGluR1a-like immunoreactivity. Approximately 65% of striatal choline acetyltransferase-immunoreactive neurons expressed mGluR5-like immunoreactivity. A majority (65%) of somatostatin-immunoreactive striatal interneurons expressed mGluR1a-like immunoreactivity with a slightly lower percentage (55%) expressing mGluR5-like immunoreactivity. These findings indicate considerable heterogeneity among striatal projection and interneurons with respect to mGluR1a and mGluR5 expression. There may be subpopulations of striatonigral and striatopallidal projection neurons. These results are consistent as well with prior data indicating subpopulations of the different classes of striatal interneurons.