Ronald Pearce | Imperial College London (original) (raw)

Papers by Ronald Pearce

Acta neuropathologica communications, 2015

Depletion of cholinergic neurons within the nucleus basalis of Meynert (nbM) is thought to contri... more Depletion of cholinergic neurons within the nucleus basalis of Meynert (nbM) is thought to contribute to the development of cognitive impairments in both Alzheimer's disease (AD) and Lewy body disorders (LBD). It has been reported that, in late stage AD, a network of fibres that contain the neuropeptide galanin displays significant hypertrophy and 'hyperinnervates' the surviving cholinergic neurons. Galanin is considered as a highly inducible neuroprotective factor and in AD this is assumed to be part of a protective tissue response. The aim of this study was to determine if a similar galanin upregulation is present in the nbM in post-mortem tissue from patients with LBD. Gallatin immunohistochemistry was carried out on anterior nbM sections from 76 LBD cases (27 PD, 15 PD with mild cognitive impairment (MCI), 34 PD with dementia (PDD) and 4 aged-matched controls. Galaninergic innervation of cholinergic neurons was assessed on a semi-quantitative scale. The LBD group had...

Journal of neuroscience research, Jan 11, 2016

The neuropathology of subcortical nuclei has received little attention in schizophrenia (SZ). Dec... more The neuropathology of subcortical nuclei has received little attention in schizophrenia (SZ). Decreased volume and neuron size have been reported for the mediodorsal thalamus, caudate, and putamen, and a total mean neuron decrease has been reported for the basolateral amygdala (BLA; Byne et al., 2002; Kreczmanski et al., 2007). Lying inferior to the parahippocampal gyrus and anterior to the hippocampus, the amygdala is involved in functions such as analyzing the emotional significance of a stimulus and coordinating the actions of a variety of brain systems (Nolte, 2002). The amygdala is a key nucleus of the limbic system and is thought to play an important role in recognition and generation of emotion. It is thought to identify emotional and motivational values of sensory inputs and to process interpretation of fear-related stimulus from others and the environment (Siegle et al., 2007). The amygdala has been implicated in emotional processing abnormalities observed in patients with schizophrenia (Shayegan and Stahl, 2005; Berretta et al., 2007) and with depression (Caetano et al., 2004; Munn et al., 2007). The amygdala contains a heterogeneous collection of nuclei, functionally grouped into basolateral, corticomedial, and olfactory clusters. The nuclei of the amygdala are reciprocally connected to the hypothalamus, brainstem, hippocampus, thalamus, and neocortex. The BLA receives sensory information from the prefrontal, temporal, insular, and occipital cortices and direct cholinergic input from the nucleus basalis. The corticoor centromedial nucleus (CMA) receives inputs from the hippocampus, insula, and orbitofrontal cortex. Amygdala dysfunction may contribute to affective symptoms observed in SZ and major depressive disorder (MDD). In humans, the primary amygdala regions are the basolateral region/nucleus (basal, lateral, and accessory basal nuclei) and the corticomedial region/nucleus (cortical, medial, and central nuclei). The basolateral region is proximal to the lateral ventricle and the entorhinal cortex and is considered the deeper nuclear group, whereas the more superficial corticomedial group is in the part of the amygdala just below the striatum, as shown in Figure 1. It is difficult to establish clear cytoarchitectural definitions for these regions because there is no consistent nomenclature among research groups (McDonald, 1998; Campbell et al., 2006). The basolateral nucleus has spiny pyramidallike neurons and spine-sparse stellate cells, thus resembling the nearby entorhinal cortex. Neurons in the central nucleus (corticomedial) group resemble the mediumsized spiny neurons of the striatum, and oval cells make up the majority of the corticomedial nucleus (McDonald, 1998). In Figure 1, the basolateral region is defined as the subnuclei and labeled “ba” and “la,” and the corticomedial nuclei are labeled “me” and “co.” For SZ, functional imaging has demonstrated increased amygdala activity when subjects are shown both neutral and fearful faces (Gur et al., 2002). Meta-analysis

Exp Neurol, 2003

The current concept of dyskinesia is that pulsatile stimulation of D-1 or D-2 receptors by L-DOPA... more The current concept of dyskinesia is that pulsatile stimulation of D-1 or D-2 receptors by L-DOPA or short-acting dopamine agonists is more likely to induce dyskinesia compared to long-acting drugs producing more continuous receptor stimulation. We now investigate the ability of two mixed D-1/D-2 agonists, namely pergolide (long-acting) and apomorphine (short-acting), to induce dyskinesia in drugnaïve MPTP-lesioned primates, compared to L-DOPA. Adult common marmosets (Callithrix jacchus) were lesioned with MPTP (2 mg/kg/day sc for 5 days) and subsequently treated with equieffective antiparkinsonian doses of L-DOPA, apomorphine, or pergolide for 28 days. L-DOPA, apomorphine, and pergolide reversed the MPTP-induced motor deficits to the same degree with no difference in peak response. L-DOPA and apomorphine had a rapid onset of action and short duration of effect producing a pulsatile motor response, while pergolide had a slow onset and long-lasting activity producing a continuous profile of motor stimulation. L-DOPA rapidly induced dyskinesia that increased markedly in severity and frequency over the course of the study, impairing normal motor activity by day 20. Dyskinesia in animals treated with pergolide or apomorphine increased steadily, reaching mild to moderate severity but remaining significantly less marked than that produced by L-DOPA. There was no difference in the intensity of dyskinesia produced by apomorphine and pergolide. These data suggest that factors other than duration of drug action may be important in the induction of dyskinesia but support the use of dopamine agonists in early Parkinson's disease, as a means of delaying L-DOPA therapy and reducing the risk of developing dyskinesia.

Neuropathology and Applied Neurobiology, 2015

Aims: CLARITY is a novel technique which enables three-dimensional visualisation of immunostained... more Aims: CLARITY is a novel technique which enables three-dimensional visualisation of immunostained tissue for the study of circuitry and spatial interactions between cells and molecules in the brain. In this study we aimed to compare methodological differences in the application of CLARITY between rodent and large human post-mortem brain samples. In addition, we aimed to investigate if this technique could be used to visualise Lewy pathology in a post-mortem Parkinson's brain. Methods: Rodent and human brain samples were clarified and immunostained using the passive version of the CLARITY technique. Samples were then immersed in different refractive index matching media before mounting and visualising under a confocal microscope. Results: We found that tissue clearing speed using passive CLARITY differs according to species (human vs rodents), brain region and degree of fixation (fresh vs formalin-fixed tissues). Furthermore, there were advantages to using specific refractive index matching media. We have applied this technique and have successfully visualised Lewy body inclusions in three dimensions within the nucleus basalis of Meynert, and the spatial relationship between monoaminergic fibres Accepted Article This article is protected by copyright. All rights reserved. and Lewy pathologies among nigrostriatal fibres in the midbrain without the need for physical serial sectioning of brain tissue. Conclusions: The effective use of CLARITY on large samples of human tissue opens up many potential avenues for detailed pathological and morphological studies.

The cholinergic neurons of the nucleus basalis of Meynert (nbM) are severely depleted in Parkinso... more The cholinergic neurons of the nucleus basalis of Meynert (nbM) are severely depleted in Parkinson's disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). The resultant cholinergic deficits are considered as a key neuropathological substrate of cognitive deterioration. Galanin, a multi-functional neuropeptide, is found in fibers that innervate the nbM and, in late stage AD, these galanin-containing fibers are reported to enlarge and hyper-innervate the surviving cholinergic neurons of the nbM. The aim of this study was to determine if a similar phenomenon could be observed in the basal forebrain of patients with Lewy body disorders (LBD). Galanin immunostaining was carried out on basal forebrain sections from 39 cases (15 PD, 16 PDD, 5 DLB, 3 mixed PD/AD) and 6 aged-matched controls from the Parkinson's UK brain bank. Hyper-innervation of the nbM neurons was evident only in a minority of cases and there were no differences in the ...

Acta Neuropathologica Communications, 2014

Background: Microglial activation is a pathological feature common to both Alzheimer's and Parkin... more Background: Microglial activation is a pathological feature common to both Alzheimer's and Parkinson's diseases (AD and PD). The classical activation involves release of pro-inflammatory cytokines and reactive oxygen species. This is necessary for maintenance of tissue homeostasis and host defense, but can cause bystander damage when the activation is sustained and uncontrolled. In recent years the heterogeneous nature of microglial activation states in neurodegenerative diseases has become clear and the focus has shifted to alternative activation states that promote tissue maintenance and repair. We studied the distribution of CD163, a membrane-bound scavenger receptor found on perivascular macrophages. CD163 has an immunoregulatory function, and has been found in the parenchyma in other inflammatory diseases e.g. HIV-encephalitis and multiple sclerosis. In this study, we used immunohistochemistry to compare CD163 immunoreactivity in 31 AD cases, 27 PD cases, and 16 control cases. Associations of microglia with pathological hallmarks of AD and PD were investigated using double immunofluorescence. Results: Parenchymal microglia were found to be immunoreactive for CD163 in all of the AD cases, and to a lesser extent in PD cases. There was prominent staining of CD163 immunoreactive microglia in the frontal and occipital cortices of AD cases, and in the brainstem of PD cases. Many of them were associated with Aß plaques in both diseases, and double staining with CD68 demonstrates their phagocytic capability. Leakage of fibrinogen was observed around compromised blood vessels, raising the possibility these microglia might have originated from the periphery. Conclusions: Increase in microglia's CD163 immunoreactivity was more significant in AD than PD, and association of CD163 immunoreactive microglia with Aβ plaques indicate microglia's attraction towards extracellular protein pathology, i.e. extracellular aggregates of Aβ as compared to intracellular Lewy Bodies in PD. Double staining with CD163 and CD68 might point towards their natural inclination to phagocytose plaques. Fibrinogen leakage and compromise of the blood brain barrier raise the possibility that these are not resident microglia, but systemic macrophages infiltrating the brain.

The Northwest Fisheries Science Center of the National Marine Fisheries Service, NOAA, uses the N... more The Northwest Fisheries Science Center of the National Marine Fisheries Service, NOAA, uses the NOAA Technical Memorandum NMFS series to issue informal scientific and technical publications when complete formal review and editorial processing are not appropriate or feasible due to time constraints. Documents published in this series may be referenced in the scientific and technical literature.

Physiology & Behavior, 1984

Mapping rnidbrain sites for circling using currentfrequency trade off data. PHYSIOL BEHAV 32(2) 2... more Mapping rnidbrain sites for circling using currentfrequency trade off data. PHYSIOL BEHAV 32(2) 287-294, 1984.-Electrical stimulation applied near the medial longitudinal fasciculus (MLF) produces ipsiversive circling. In this experiment we examined the spatial and temporal properties of this substrate in rats by determining the current required to produce a constant amount of circling at frequencies from 15 to 500 Hz. In general, when frequency was high, the required current was low and vice versa, but there were deviations from a reciprocal relationship. Frequencies above 200 Hz failed to reduce the current needed to reach criterion. Electrodes placed distant from the MLF required more current, and deviated from reciprocity in a systematic way. A geometric model of the overlap between substrate and stimulation field is proposed that allows estimation of spatial properties of the two regions: (1) the location of the center of the substrate for circling (0.7 mm lateral, 7.0 mm below dura in the coronal plane 1.0 mm posterior to ear bars); (2) the radius of the substrate (0.77 mm); and (3) the radius of excitation at each current. Currentfrequency trade off data can provide an in vivo estimate of the behavioral effectiveness of a given electrode, and hence its placement relative to a behavioral substrate. Brain stimulation Circling Geometric model Current-distance relationship Frequency following

Pharmacology Biochemistry and Behavior, 2004

An interaction between brain serotonergic and dopaminergic systems involving 5-HT(1B) receptors m... more An interaction between brain serotonergic and dopaminergic systems involving 5-HT(1B) receptors may contribute to motor complications arising from the drug treatment of neurological and psychiatric disorders. This study assessed the effects of treatment with a non-selective 5-HT(1B/D) receptor agonist and a selective 5-HT(1B) receptor antagonist on akinesia induced in marmosets by long-term treatment with haloperidol and on motor disability and l-3, 4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets. In marmosets treated chronically with haloperidol, the 5-HT(1B) agonist SKF-99101-H reduced locomotor activity and induced motor disability, whereas the 5-HT(1B) antagonist SB-224289-A had no effect on motor behaviour. Haloperidol administration induced a suppression of locomotor activity which was not reversed by co-administration of either SKF-99101-H or SB-224289-A. In MPTP-treated common marmosets, neither SKF-99101-H nor SB-224289-A induced any significant change in motor function. However, SKF-99101-H inhibited L-DOPA-induced dyskinesia and the reversal of motor deficits whereas SB-224289-A was without effect. The results of this study indicate that the 5-HT(1B) receptor appears not to be an appropriate target for the treatment of Parkinson's disease (PD) or for the control of drug-induced motor complications developed as a tong-term consequence of neuroleptic or L-DOPA treatment.

North American Journal of Aquaculture, 2010

... 199336. Lauenstein, GG, Cantillo, AY and Dolvin, SS 1993. National Oceanic and Atmospheric Ad... more ... 199336. Lauenstein, GG, Cantillo, AY and Dolvin, SS 1993. National Oceanic and Atmospheric Administration national status and trends program development and methods. NOAA Technical Memorandum NOS-ORCA-71 , 1 View all references). ...

Neuroscience Research, 1997

Tomoyuki Kanda ly2 Michael J. Jacksoni, Lance Smithl, Ronald K.B. Pearce’, Hiroshi Kase2, Yoshihi... more Tomoyuki Kanda ly2 Michael J. Jacksoni, Lance Smithl, Ronald K.B. Pearce’, Hiroshi Kase2, Yoshihisa , Kuwana1t2, Peter Jenner’ Antiparkinsonian activity of adenosine Aso antagonists were investigated with MPTP-treated primates. Oral administration of adenosine Aga antagonists improved parkinsonian symptoms in MPTP-treated common marmosets. Adenosine Aao antagonists did not cause the hyperactivity and neither tolerance nor dyskinesias were observed at chronic treatment of adenosine Asa antagonist in MPTP-treated common marmosets. Adenosine Aza antagonists may provide a novel non-dopaminergic therapeutic approach to the Parkinson’s disease while these modulate motor function, and show the antiparkinsonian activity in MPTP-treated primates.

neurogenetics, 2011

The role of glial cells in Parkinson's disease (PD) is unclear. We have previously reported a str... more The role of glial cells in Parkinson's disease (PD) is unclear. We have previously reported a striking up-regulation of DnaJB6 heat shock protein in PD substantia nigra astrocytes. Whole genome transcriptome analysis also indicated increased expression of metallothionein genes in substantia nigra and cortex of sporadic PD cases. Metallothioneins are metal-binding proteins in the CNS that are released by astrocytes and associated with neuroprotection. Metallothionein expression was investigated in 18 PD cases and 15 non-PD controls using quantitative real-time polymerase chain reaction (qRT-PCR), in situ hybridisation (ISH) and immunocytochemistry (ICC). We observed a strong increase in the expression of metallothioneins MT1E, MT1F, MT1G, MT1H, MT1M, MT1X and MT2A in both PD nigra and frontal cortex. Expression of LRP2 (megalin), the neuronal metallothionein receptor was also significantly increased. qRT-PCR confirmed metallothionein up-regulation. Astrocytes were found to be the main source of metallothioneins 1 and 2 based on ISH results, and this finding was confirmed by ICC. Our findings demonstrate metallothionein expression by reactive astrocytes in PD nigra and support a neuroprotective role for these cells. The traditional view that nigral astrocytes are non-reactive in PD is clearly incorrect. However, it is possible that astrocytes are themselves affected by the disease process which may explain their comparatively modest and previously overlooked response.

Movement Disorders, 2002

The common marmoset develops motor deficits after MPTP treatment and exhibits dyskinesia after ch... more The common marmoset develops motor deficits after MPTP treatment and exhibits dyskinesia after chronic levodopa (L-dopa) dosing and subsequent re-challenge with L-dopa and other dopaminergic agents. We report on the actions of the potent monoamine reuptake blocker brasofensine on motor disability, locomotor activity, and dyskinesia in the 1-methyl-4-1, 2,3,6-tetrahydropyridine (MPTP) -treated marmoset model of Parkinson's disease. Oral administration of brasofensine (0.25, 0.5, 1.0, or 2.5 mg/kg) to MPTP-treated marmosets produced a long-lasting, dose-dependent increase in locomotor activity and reduction in disability scores. In addition, coadministration of the lowest dose of brasofensine (0.25 mg/kg orally) with a threshold oral dose of L-dopa (2.5 mg/kg) caused a marked increase in locomotor activity, greater than that produced by either drug alone. In other MPTP-treated marmosets previously primed to exhibit dyskinesia by repeated L-dopa dosing, brasofensine effectively reversed akinesia with a naturalistic and prolonged motor response without the appearance of dyskinesia or stereotypy. This finding contrasts with the severe dyskinesia, stereotypy, and hyperkinesis produced by equivalent doses of L-dopa. The ability of brasofensine to produce a prolonged and naturalistic antiparkinsonian response without eliciting dyskinesia after previous L-dopa priming may relate to actions on D(1) receptor-linked pathways. These findings suggest that monoamine reuptake blockade may be of value in the treatment of Parkinson's disease, both early in the disease course and when L-dopa-induced dyskinesias complicate treatment.

Movement Disorders, 2001

De novo administration of long-acting dopamine agonists, such as ropinirole, to patients with Par... more De novo administration of long-acting dopamine agonists, such as ropinirole, to patients with Parkinson's disease or to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated subhuman primates produces a lower incidence of dyskinesia than occurs with levodopa (L-DOPA). This study compares the intensity of dyskinesia produced by combinations of L-DOPA and ropinirole and by these drugs alone, using the MPTP-treated common marmoset model of Parkinson's disease. The objective is to determine the optimum therapeutic strategy for the long-term control of Parkinson's disease with a minimal risk of dyskinesia. MPTP-treated marmosets received either L-DOPA alone, ropinirole alone, or one of two combinations of these drugs (either L-DOPA dominant or ropinirole dominant) daily for 28 days in doses titrated to produce a similar improvement in disability and increase in locomotion. In the group receiving L-DOPA alone, there was a trend for peak dose locomotor activity to increase and the duration of drug effect to decline over the period of the study. L-DOPA alone induced marked dyskinesia over the period of treatment, in contrast to ropinirole which produced a low intensity of involuntary movements. The L-DOPA dominant combination initially produced little dyskinesia, but this became increasingly intense as the study progressed. In contrast, the ropinirole dominant combination produced no greater intensity of dyskinesia than was produced by ropinirole alone. These data suggest that in early Parkinson's disease, the use of ropinirole alone or in combination with a low-dose L-DOPA might delay the induction of dyskinesias while improving motor performance.

Movement Disorders, 2003

Tremor is one of the cardinal signs of Parkinson&... more Tremor is one of the cardinal signs of Parkinson's disease (PD) but its response to antiparkinsonian medication is variable. It has been postulated that pramipexole may have a stronger antiparkinsonian tremor effect than pergolide, another direct acting dopamine agonist medication, possibly because the former has preferential affinity for the dopamine D3 receptor. The purpose of this pilot study was to compare the effects of a single oral dose of either pramipexole (Pr) or pergolide (Pe) or placebo (Pl) on parkinsonian tremor and the motor (part III) subsection of the UPDRS. Ten patients (6 men, 4 women), mean age 65.3 years, mean duration from diagnosis of 2.6 years, with tremor dominant PD were recruited. On three separate occasions a single dose of pramipexole (salt) 500 microg, pergolide 500 microg or placebo were administered in random order to each patient, who were pretreated with domperidone and had their antiparkinsonian medication withheld from midnight before study. After each medication patients were assessed at baseline and then every 30 min for 4 hr using a 0 to 10 tremor rating scale and the UPDRS (part III) in a double-blind protocol. Adverse effects were systematically recorded. The results demonstrate that 500 microg of either pramipexole or pergolide reduced PD rest tremor scores to a similar degree, which at peak effect was significantly greater than placebo (respectively Pe v Pl: P < 0.006, Pr v Pl: P < 0.033). The two active drugs also had weaker beneficial effects on the UPDRS part III. Pergolide, however, was significantly more likely than pramipexole to cause nausea (P = 0.005) or vomiting (P = 0.014).

Marine Mammal Science, 2008

Measuring chemical tracers in tissues of marine predators provides insight into the prey consumed... more Measuring chemical tracers in tissues of marine predators provides insight into the prey consumed and the predator's contaminant exposure. In this study, samples from Type C killer whales (Orcinus orca) biopsied in Antarctica were analyzed for chemical tracers (i.e., stable isotopes of carbon and nitrogen, fatty acids, and persistent organic pollutants [POPs]). Profiles of these individual tracers were very different from those of killer whale populations that have been studied in the eastern North and eastern Tropical Pacific. For example, ␦ 13 C and ␦ 15 N stable isotope values and most POP concentrations were significantly lower in the Antarctic population. In addition, multivariate statistical analyses of both fatty acid and POP profiles found distinctly different patterns for Antarctic Type C whales compared to those from whales in the other populations. Similar assays were conducted on four species of Antarctic marine fish considered potential prey for Type C killer whales. Results were consistent with a diet of fish for Type C whales, but other species (e.g., low trophic-level marine mammals or penguins) could not be eliminated as supplemental prey.

Marine Ecology Progress Series, 2008

International Clinical Psychopharmacology, 2011

International Clinical Psychopharmacology, 2011

Acta neuropathologica communications, 2015

Depletion of cholinergic neurons within the nucleus basalis of Meynert (nbM) is thought to contri... more Depletion of cholinergic neurons within the nucleus basalis of Meynert (nbM) is thought to contribute to the development of cognitive impairments in both Alzheimer's disease (AD) and Lewy body disorders (LBD). It has been reported that, in late stage AD, a network of fibres that contain the neuropeptide galanin displays significant hypertrophy and 'hyperinnervates' the surviving cholinergic neurons. Galanin is considered as a highly inducible neuroprotective factor and in AD this is assumed to be part of a protective tissue response. The aim of this study was to determine if a similar galanin upregulation is present in the nbM in post-mortem tissue from patients with LBD. Gallatin immunohistochemistry was carried out on anterior nbM sections from 76 LBD cases (27 PD, 15 PD with mild cognitive impairment (MCI), 34 PD with dementia (PDD) and 4 aged-matched controls. Galaninergic innervation of cholinergic neurons was assessed on a semi-quantitative scale. The LBD group had...

Journal of neuroscience research, Jan 11, 2016

The neuropathology of subcortical nuclei has received little attention in schizophrenia (SZ). Dec... more The neuropathology of subcortical nuclei has received little attention in schizophrenia (SZ). Decreased volume and neuron size have been reported for the mediodorsal thalamus, caudate, and putamen, and a total mean neuron decrease has been reported for the basolateral amygdala (BLA; Byne et al., 2002; Kreczmanski et al., 2007). Lying inferior to the parahippocampal gyrus and anterior to the hippocampus, the amygdala is involved in functions such as analyzing the emotional significance of a stimulus and coordinating the actions of a variety of brain systems (Nolte, 2002). The amygdala is a key nucleus of the limbic system and is thought to play an important role in recognition and generation of emotion. It is thought to identify emotional and motivational values of sensory inputs and to process interpretation of fear-related stimulus from others and the environment (Siegle et al., 2007). The amygdala has been implicated in emotional processing abnormalities observed in patients with schizophrenia (Shayegan and Stahl, 2005; Berretta et al., 2007) and with depression (Caetano et al., 2004; Munn et al., 2007). The amygdala contains a heterogeneous collection of nuclei, functionally grouped into basolateral, corticomedial, and olfactory clusters. The nuclei of the amygdala are reciprocally connected to the hypothalamus, brainstem, hippocampus, thalamus, and neocortex. The BLA receives sensory information from the prefrontal, temporal, insular, and occipital cortices and direct cholinergic input from the nucleus basalis. The corticoor centromedial nucleus (CMA) receives inputs from the hippocampus, insula, and orbitofrontal cortex. Amygdala dysfunction may contribute to affective symptoms observed in SZ and major depressive disorder (MDD). In humans, the primary amygdala regions are the basolateral region/nucleus (basal, lateral, and accessory basal nuclei) and the corticomedial region/nucleus (cortical, medial, and central nuclei). The basolateral region is proximal to the lateral ventricle and the entorhinal cortex and is considered the deeper nuclear group, whereas the more superficial corticomedial group is in the part of the amygdala just below the striatum, as shown in Figure 1. It is difficult to establish clear cytoarchitectural definitions for these regions because there is no consistent nomenclature among research groups (McDonald, 1998; Campbell et al., 2006). The basolateral nucleus has spiny pyramidallike neurons and spine-sparse stellate cells, thus resembling the nearby entorhinal cortex. Neurons in the central nucleus (corticomedial) group resemble the mediumsized spiny neurons of the striatum, and oval cells make up the majority of the corticomedial nucleus (McDonald, 1998). In Figure 1, the basolateral region is defined as the subnuclei and labeled “ba” and “la,” and the corticomedial nuclei are labeled “me” and “co.” For SZ, functional imaging has demonstrated increased amygdala activity when subjects are shown both neutral and fearful faces (Gur et al., 2002). Meta-analysis

Exp Neurol, 2003

The current concept of dyskinesia is that pulsatile stimulation of D-1 or D-2 receptors by L-DOPA... more The current concept of dyskinesia is that pulsatile stimulation of D-1 or D-2 receptors by L-DOPA or short-acting dopamine agonists is more likely to induce dyskinesia compared to long-acting drugs producing more continuous receptor stimulation. We now investigate the ability of two mixed D-1/D-2 agonists, namely pergolide (long-acting) and apomorphine (short-acting), to induce dyskinesia in drugnaïve MPTP-lesioned primates, compared to L-DOPA. Adult common marmosets (Callithrix jacchus) were lesioned with MPTP (2 mg/kg/day sc for 5 days) and subsequently treated with equieffective antiparkinsonian doses of L-DOPA, apomorphine, or pergolide for 28 days. L-DOPA, apomorphine, and pergolide reversed the MPTP-induced motor deficits to the same degree with no difference in peak response. L-DOPA and apomorphine had a rapid onset of action and short duration of effect producing a pulsatile motor response, while pergolide had a slow onset and long-lasting activity producing a continuous profile of motor stimulation. L-DOPA rapidly induced dyskinesia that increased markedly in severity and frequency over the course of the study, impairing normal motor activity by day 20. Dyskinesia in animals treated with pergolide or apomorphine increased steadily, reaching mild to moderate severity but remaining significantly less marked than that produced by L-DOPA. There was no difference in the intensity of dyskinesia produced by apomorphine and pergolide. These data suggest that factors other than duration of drug action may be important in the induction of dyskinesia but support the use of dopamine agonists in early Parkinson's disease, as a means of delaying L-DOPA therapy and reducing the risk of developing dyskinesia.

Neuropathology and Applied Neurobiology, 2015

Aims: CLARITY is a novel technique which enables three-dimensional visualisation of immunostained... more Aims: CLARITY is a novel technique which enables three-dimensional visualisation of immunostained tissue for the study of circuitry and spatial interactions between cells and molecules in the brain. In this study we aimed to compare methodological differences in the application of CLARITY between rodent and large human post-mortem brain samples. In addition, we aimed to investigate if this technique could be used to visualise Lewy pathology in a post-mortem Parkinson's brain. Methods: Rodent and human brain samples were clarified and immunostained using the passive version of the CLARITY technique. Samples were then immersed in different refractive index matching media before mounting and visualising under a confocal microscope. Results: We found that tissue clearing speed using passive CLARITY differs according to species (human vs rodents), brain region and degree of fixation (fresh vs formalin-fixed tissues). Furthermore, there were advantages to using specific refractive index matching media. We have applied this technique and have successfully visualised Lewy body inclusions in three dimensions within the nucleus basalis of Meynert, and the spatial relationship between monoaminergic fibres Accepted Article This article is protected by copyright. All rights reserved. and Lewy pathologies among nigrostriatal fibres in the midbrain without the need for physical serial sectioning of brain tissue. Conclusions: The effective use of CLARITY on large samples of human tissue opens up many potential avenues for detailed pathological and morphological studies.

The cholinergic neurons of the nucleus basalis of Meynert (nbM) are severely depleted in Parkinso... more The cholinergic neurons of the nucleus basalis of Meynert (nbM) are severely depleted in Parkinson's disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). The resultant cholinergic deficits are considered as a key neuropathological substrate of cognitive deterioration. Galanin, a multi-functional neuropeptide, is found in fibers that innervate the nbM and, in late stage AD, these galanin-containing fibers are reported to enlarge and hyper-innervate the surviving cholinergic neurons of the nbM. The aim of this study was to determine if a similar phenomenon could be observed in the basal forebrain of patients with Lewy body disorders (LBD). Galanin immunostaining was carried out on basal forebrain sections from 39 cases (15 PD, 16 PDD, 5 DLB, 3 mixed PD/AD) and 6 aged-matched controls from the Parkinson's UK brain bank. Hyper-innervation of the nbM neurons was evident only in a minority of cases and there were no differences in the ...

Acta Neuropathologica Communications, 2014

Background: Microglial activation is a pathological feature common to both Alzheimer's and Parkin... more Background: Microglial activation is a pathological feature common to both Alzheimer's and Parkinson's diseases (AD and PD). The classical activation involves release of pro-inflammatory cytokines and reactive oxygen species. This is necessary for maintenance of tissue homeostasis and host defense, but can cause bystander damage when the activation is sustained and uncontrolled. In recent years the heterogeneous nature of microglial activation states in neurodegenerative diseases has become clear and the focus has shifted to alternative activation states that promote tissue maintenance and repair. We studied the distribution of CD163, a membrane-bound scavenger receptor found on perivascular macrophages. CD163 has an immunoregulatory function, and has been found in the parenchyma in other inflammatory diseases e.g. HIV-encephalitis and multiple sclerosis. In this study, we used immunohistochemistry to compare CD163 immunoreactivity in 31 AD cases, 27 PD cases, and 16 control cases. Associations of microglia with pathological hallmarks of AD and PD were investigated using double immunofluorescence. Results: Parenchymal microglia were found to be immunoreactive for CD163 in all of the AD cases, and to a lesser extent in PD cases. There was prominent staining of CD163 immunoreactive microglia in the frontal and occipital cortices of AD cases, and in the brainstem of PD cases. Many of them were associated with Aß plaques in both diseases, and double staining with CD68 demonstrates their phagocytic capability. Leakage of fibrinogen was observed around compromised blood vessels, raising the possibility these microglia might have originated from the periphery. Conclusions: Increase in microglia's CD163 immunoreactivity was more significant in AD than PD, and association of CD163 immunoreactive microglia with Aβ plaques indicate microglia's attraction towards extracellular protein pathology, i.e. extracellular aggregates of Aβ as compared to intracellular Lewy Bodies in PD. Double staining with CD163 and CD68 might point towards their natural inclination to phagocytose plaques. Fibrinogen leakage and compromise of the blood brain barrier raise the possibility that these are not resident microglia, but systemic macrophages infiltrating the brain.

The Northwest Fisheries Science Center of the National Marine Fisheries Service, NOAA, uses the N... more The Northwest Fisheries Science Center of the National Marine Fisheries Service, NOAA, uses the NOAA Technical Memorandum NMFS series to issue informal scientific and technical publications when complete formal review and editorial processing are not appropriate or feasible due to time constraints. Documents published in this series may be referenced in the scientific and technical literature.

Physiology & Behavior, 1984

Mapping rnidbrain sites for circling using currentfrequency trade off data. PHYSIOL BEHAV 32(2) 2... more Mapping rnidbrain sites for circling using currentfrequency trade off data. PHYSIOL BEHAV 32(2) 287-294, 1984.-Electrical stimulation applied near the medial longitudinal fasciculus (MLF) produces ipsiversive circling. In this experiment we examined the spatial and temporal properties of this substrate in rats by determining the current required to produce a constant amount of circling at frequencies from 15 to 500 Hz. In general, when frequency was high, the required current was low and vice versa, but there were deviations from a reciprocal relationship. Frequencies above 200 Hz failed to reduce the current needed to reach criterion. Electrodes placed distant from the MLF required more current, and deviated from reciprocity in a systematic way. A geometric model of the overlap between substrate and stimulation field is proposed that allows estimation of spatial properties of the two regions: (1) the location of the center of the substrate for circling (0.7 mm lateral, 7.0 mm below dura in the coronal plane 1.0 mm posterior to ear bars); (2) the radius of the substrate (0.77 mm); and (3) the radius of excitation at each current. Currentfrequency trade off data can provide an in vivo estimate of the behavioral effectiveness of a given electrode, and hence its placement relative to a behavioral substrate. Brain stimulation Circling Geometric model Current-distance relationship Frequency following

Pharmacology Biochemistry and Behavior, 2004

An interaction between brain serotonergic and dopaminergic systems involving 5-HT(1B) receptors m... more An interaction between brain serotonergic and dopaminergic systems involving 5-HT(1B) receptors may contribute to motor complications arising from the drug treatment of neurological and psychiatric disorders. This study assessed the effects of treatment with a non-selective 5-HT(1B/D) receptor agonist and a selective 5-HT(1B) receptor antagonist on akinesia induced in marmosets by long-term treatment with haloperidol and on motor disability and l-3, 4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets. In marmosets treated chronically with haloperidol, the 5-HT(1B) agonist SKF-99101-H reduced locomotor activity and induced motor disability, whereas the 5-HT(1B) antagonist SB-224289-A had no effect on motor behaviour. Haloperidol administration induced a suppression of locomotor activity which was not reversed by co-administration of either SKF-99101-H or SB-224289-A. In MPTP-treated common marmosets, neither SKF-99101-H nor SB-224289-A induced any significant change in motor function. However, SKF-99101-H inhibited L-DOPA-induced dyskinesia and the reversal of motor deficits whereas SB-224289-A was without effect. The results of this study indicate that the 5-HT(1B) receptor appears not to be an appropriate target for the treatment of Parkinson's disease (PD) or for the control of drug-induced motor complications developed as a tong-term consequence of neuroleptic or L-DOPA treatment.

North American Journal of Aquaculture, 2010

... 199336. Lauenstein, GG, Cantillo, AY and Dolvin, SS 1993. National Oceanic and Atmospheric Ad... more ... 199336. Lauenstein, GG, Cantillo, AY and Dolvin, SS 1993. National Oceanic and Atmospheric Administration national status and trends program development and methods. NOAA Technical Memorandum NOS-ORCA-71 , 1 View all references). ...

Neuroscience Research, 1997

Tomoyuki Kanda ly2 Michael J. Jacksoni, Lance Smithl, Ronald K.B. Pearce’, Hiroshi Kase2, Yoshihi... more Tomoyuki Kanda ly2 Michael J. Jacksoni, Lance Smithl, Ronald K.B. Pearce’, Hiroshi Kase2, Yoshihisa , Kuwana1t2, Peter Jenner’ Antiparkinsonian activity of adenosine Aso antagonists were investigated with MPTP-treated primates. Oral administration of adenosine Aga antagonists improved parkinsonian symptoms in MPTP-treated common marmosets. Adenosine Aao antagonists did not cause the hyperactivity and neither tolerance nor dyskinesias were observed at chronic treatment of adenosine Asa antagonist in MPTP-treated common marmosets. Adenosine Aza antagonists may provide a novel non-dopaminergic therapeutic approach to the Parkinson’s disease while these modulate motor function, and show the antiparkinsonian activity in MPTP-treated primates.

neurogenetics, 2011

The role of glial cells in Parkinson's disease (PD) is unclear. We have previously reported a str... more The role of glial cells in Parkinson's disease (PD) is unclear. We have previously reported a striking up-regulation of DnaJB6 heat shock protein in PD substantia nigra astrocytes. Whole genome transcriptome analysis also indicated increased expression of metallothionein genes in substantia nigra and cortex of sporadic PD cases. Metallothioneins are metal-binding proteins in the CNS that are released by astrocytes and associated with neuroprotection. Metallothionein expression was investigated in 18 PD cases and 15 non-PD controls using quantitative real-time polymerase chain reaction (qRT-PCR), in situ hybridisation (ISH) and immunocytochemistry (ICC). We observed a strong increase in the expression of metallothioneins MT1E, MT1F, MT1G, MT1H, MT1M, MT1X and MT2A in both PD nigra and frontal cortex. Expression of LRP2 (megalin), the neuronal metallothionein receptor was also significantly increased. qRT-PCR confirmed metallothionein up-regulation. Astrocytes were found to be the main source of metallothioneins 1 and 2 based on ISH results, and this finding was confirmed by ICC. Our findings demonstrate metallothionein expression by reactive astrocytes in PD nigra and support a neuroprotective role for these cells. The traditional view that nigral astrocytes are non-reactive in PD is clearly incorrect. However, it is possible that astrocytes are themselves affected by the disease process which may explain their comparatively modest and previously overlooked response.

Movement Disorders, 2002

The common marmoset develops motor deficits after MPTP treatment and exhibits dyskinesia after ch... more The common marmoset develops motor deficits after MPTP treatment and exhibits dyskinesia after chronic levodopa (L-dopa) dosing and subsequent re-challenge with L-dopa and other dopaminergic agents. We report on the actions of the potent monoamine reuptake blocker brasofensine on motor disability, locomotor activity, and dyskinesia in the 1-methyl-4-1, 2,3,6-tetrahydropyridine (MPTP) -treated marmoset model of Parkinson's disease. Oral administration of brasofensine (0.25, 0.5, 1.0, or 2.5 mg/kg) to MPTP-treated marmosets produced a long-lasting, dose-dependent increase in locomotor activity and reduction in disability scores. In addition, coadministration of the lowest dose of brasofensine (0.25 mg/kg orally) with a threshold oral dose of L-dopa (2.5 mg/kg) caused a marked increase in locomotor activity, greater than that produced by either drug alone. In other MPTP-treated marmosets previously primed to exhibit dyskinesia by repeated L-dopa dosing, brasofensine effectively reversed akinesia with a naturalistic and prolonged motor response without the appearance of dyskinesia or stereotypy. This finding contrasts with the severe dyskinesia, stereotypy, and hyperkinesis produced by equivalent doses of L-dopa. The ability of brasofensine to produce a prolonged and naturalistic antiparkinsonian response without eliciting dyskinesia after previous L-dopa priming may relate to actions on D(1) receptor-linked pathways. These findings suggest that monoamine reuptake blockade may be of value in the treatment of Parkinson's disease, both early in the disease course and when L-dopa-induced dyskinesias complicate treatment.

Movement Disorders, 2001

De novo administration of long-acting dopamine agonists, such as ropinirole, to patients with Par... more De novo administration of long-acting dopamine agonists, such as ropinirole, to patients with Parkinson's disease or to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated subhuman primates produces a lower incidence of dyskinesia than occurs with levodopa (L-DOPA). This study compares the intensity of dyskinesia produced by combinations of L-DOPA and ropinirole and by these drugs alone, using the MPTP-treated common marmoset model of Parkinson's disease. The objective is to determine the optimum therapeutic strategy for the long-term control of Parkinson's disease with a minimal risk of dyskinesia. MPTP-treated marmosets received either L-DOPA alone, ropinirole alone, or one of two combinations of these drugs (either L-DOPA dominant or ropinirole dominant) daily for 28 days in doses titrated to produce a similar improvement in disability and increase in locomotion. In the group receiving L-DOPA alone, there was a trend for peak dose locomotor activity to increase and the duration of drug effect to decline over the period of the study. L-DOPA alone induced marked dyskinesia over the period of treatment, in contrast to ropinirole which produced a low intensity of involuntary movements. The L-DOPA dominant combination initially produced little dyskinesia, but this became increasingly intense as the study progressed. In contrast, the ropinirole dominant combination produced no greater intensity of dyskinesia than was produced by ropinirole alone. These data suggest that in early Parkinson's disease, the use of ropinirole alone or in combination with a low-dose L-DOPA might delay the induction of dyskinesias while improving motor performance.

Movement Disorders, 2003

Tremor is one of the cardinal signs of Parkinson&... more Tremor is one of the cardinal signs of Parkinson's disease (PD) but its response to antiparkinsonian medication is variable. It has been postulated that pramipexole may have a stronger antiparkinsonian tremor effect than pergolide, another direct acting dopamine agonist medication, possibly because the former has preferential affinity for the dopamine D3 receptor. The purpose of this pilot study was to compare the effects of a single oral dose of either pramipexole (Pr) or pergolide (Pe) or placebo (Pl) on parkinsonian tremor and the motor (part III) subsection of the UPDRS. Ten patients (6 men, 4 women), mean age 65.3 years, mean duration from diagnosis of 2.6 years, with tremor dominant PD were recruited. On three separate occasions a single dose of pramipexole (salt) 500 microg, pergolide 500 microg or placebo were administered in random order to each patient, who were pretreated with domperidone and had their antiparkinsonian medication withheld from midnight before study. After each medication patients were assessed at baseline and then every 30 min for 4 hr using a 0 to 10 tremor rating scale and the UPDRS (part III) in a double-blind protocol. Adverse effects were systematically recorded. The results demonstrate that 500 microg of either pramipexole or pergolide reduced PD rest tremor scores to a similar degree, which at peak effect was significantly greater than placebo (respectively Pe v Pl: P < 0.006, Pr v Pl: P < 0.033). The two active drugs also had weaker beneficial effects on the UPDRS part III. Pergolide, however, was significantly more likely than pramipexole to cause nausea (P = 0.005) or vomiting (P = 0.014).

Marine Mammal Science, 2008

Measuring chemical tracers in tissues of marine predators provides insight into the prey consumed... more Measuring chemical tracers in tissues of marine predators provides insight into the prey consumed and the predator's contaminant exposure. In this study, samples from Type C killer whales (Orcinus orca) biopsied in Antarctica were analyzed for chemical tracers (i.e., stable isotopes of carbon and nitrogen, fatty acids, and persistent organic pollutants [POPs]). Profiles of these individual tracers were very different from those of killer whale populations that have been studied in the eastern North and eastern Tropical Pacific. For example, ␦ 13 C and ␦ 15 N stable isotope values and most POP concentrations were significantly lower in the Antarctic population. In addition, multivariate statistical analyses of both fatty acid and POP profiles found distinctly different patterns for Antarctic Type C whales compared to those from whales in the other populations. Similar assays were conducted on four species of Antarctic marine fish considered potential prey for Type C killer whales. Results were consistent with a diet of fish for Type C whales, but other species (e.g., low trophic-level marine mammals or penguins) could not be eliminated as supplemental prey.

Marine Ecology Progress Series, 2008

International Clinical Psychopharmacology, 2011

International Clinical Psychopharmacology, 2011