Striatal Dopaminergic Deficits Research Articles

Cellular replacement strategies and adult neurogenesis in idiopathic Parkinson's disease

Parkinson's disease (PD) is the most common age-related movement disorder and characterized by slowly progressive neurodegeneration resulting in motor symptoms, such as bradykinesia, rigidity, tremor and postural instability. Moreover, non-motor symptoms, such as hyposmia, anxiety and depression reduce the quality of life in PD. Motor symptoms are associated with a distinct striatal dopaminergic deficit resulting from axonal dysfunction and neuronal loss in the substantia nigra (SN). Recent progress in stem cell technology allows the optimization of cellular transplantation strategies in order to alleviate the motor deficit, which potentially leads to a reactivation of this therapeutic strategy. Besides neurodegenerative processes impaired adult neurogenesis and consequentially reduced endogenous cellular plasticity may play an important role in PD. This article discusses the notion that non-motor symptoms in PD may partly be explained by reduced adult neurogenesis in the olfactory bulb and hippocampus.

COGNITIVE PERFORMANCE AND FUNCTIONAL CONNECTIVITY ARE MODULATED BY STRIATAL DOPAMINERGIC DEFICIT IN ADULTS WITH PARKINSON’S DISEASE

COGNITIVE PERFORMANCE AND FUNCTIONAL CONNECTIVITY ARE MODULATED BY STRIATAL DOPAMINERGIC DEFICIT IN ADULTS WITH PARKINSON’S DISEASE

Normal Pressure Hydrocephalus and Parkinsonism: Preliminary Data on Neurosurgical and Neurological Treatment

Idiopathic normal pressure hydrocephalus (iNPH) may present, besides the classic triad of symptoms, with extrapyramidal parkinsonianlike movement disorders. We present a randomized prospective study comparing adjustable ventriculoperitoneal (VP) shunt insertion plus dopamine oral therapy (group A) versus VP shunt alone (group B) in patients affected by iNPH associated with parkinsonism. A detailed screening process included neurologic, neurosurgical, and neuropsychological evaluations, followed by a cerebrospinal fluid tap test and resistance outflow measurement. Outcome was evaluated through the Japanese NPH Grading Scale-Revised (JNPHGSR) and the motor (third) section of the Unified Parkinson's Disease Rating Scale, Motor Section (UPDRS-m). Friedman analysis of variance with a Wilcoxon post hoc test was used to evaluate the difference in JNPHGSR and UPDRS-m scores between pretreatment and follow-up (12 months) in the 2 groups, and a Kruskal-Wallis statistic and post hoc Mann-Whitney test were used to compare the change in JNPHGSR and UPDRS-m scores between the 2 groups. Thirty-two of 54 (59%) patients (mean age, 73.2 years) screened in 36 months met the inclusion criteria, but only 30 were enrolled (2 refused surgery) (15 in each group). Preoperative (123)I-ioflupane-cerebral single-photon emission computed tomography (DaTSCAN) revealed striatal dopaminergic deficit in 14/30 patients (46.5%). At the final 12 months follow-up, both groups improved JNPHGSR and UPRDS-m scores. The UPDRS-m score improvement was significant in both groups, but greater in group A (P= 0.003); JNPHGSR score improvement was similar in the 2 groups. iNPH associated with parkinsonism may be a frequent finding. In these cases, patients may benefit from VP shunt plus dopamine oral therapy.

Apathy and striatal dopamine defects in non-demented patients with Parkinson's disease

IntroductionApathy is a common, disabling symptom in Parkinson's disease (PD). The mechanisms underlying apathy in PD are still unclear, although they may be related to dysfunction in the meso-cortico-limbic circuit, including the ventral striatum. Thus, we performed this study to investigate whether dopamine depletion in the ventral striatum contributes to apathy in PD. MethodsWe conducted a survey of the degree of apathy (using the Korean version of the Apathy Evaluation Scale, AES-S) in 108 non-demented patients with PD who underwent dopamine transporter (DAT) positron emission tomography scans as an initial diagnostic work-up. Patients with AES-S scores of 37 or higher were defined as having apathetic PD. The Beck Depression Inventory (BDI) was administered to assess the severity of depression. Patients with BDI scores of 15 or higher were regarded as having depression. ResultsApathetic patients (n = 34) tended to exhibit higher BDI scores than non-apathetic patients (n = 74); however, other clinical variables were comparable between the two groups. DAT activity in the striatal sub-regions was also similar between the two groups. Selecting only non-depressed patients, including 20 apathetic and 47 non-apathetic patients, did not alter the results. ConclusionsThis study demonstrated that the pattern of striatal dopamine depletion does not contribute to the degree of apathy in early PD. Apathy in PD may be associated with extra-striatal lesions that accompany PD rather than striatal dopaminergic deficits.

Symptômes négatifs et imagerie cérébrale

A number of neuroanatomical and neurofonctional abnormalities have been evidenced by cerebral imaging studies in patients suffering from schizophrenia. Nevertheless, those specifically associated with the negative symptoms of this disease are still insufficiently known. This work is a review of selected studies that have assessed the brain correlates of negative symptoms in schizophrenia. Approaches using structural imaging have highlighted reduction of gray matter density or cortical thickness associated with negative symptoms, which is rather sparsely distributed within the frontal and temporal regions, localized nevertheless more particularly in the frontal medial and orbitofrontal areas, as well as the amygdalo-hippocampic complex. These deficits are concurrent with a loss of integrity of the principal paths of white matter tracts between frontal and limbic regions. On the other hand, neurofonctional abnormalities associated with negative symptoms involve especially the frontal areas and limbic striatum. A disturbed functioning within the fronto-striatal loops, related to a striatal dopaminergic deficit, may represent a potential explanatory hypothesis of the negative symptoms of schizophrenia, as suggested by studies using Positron Emission Tomography on this topic or neuroimaging studies on the effects of antipsychotics. A better identification of the cerebral abnormalities associated with the negative dimension of schizophrenia, with regard to the lateralization of these abnormalities or to their changes during the course of the disease, could offer new therapeutic modalities for the treatment of this dimension which, until now, remains few responsive to conventional pharmacological treatments.

Preclinical Evidence for a Role of the Nicotinic Cholinergic System in Parkinson's Disease.

One of the primary deficits in Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra pars compacta which leads to striatal dopaminergic deficits that underlie the motor symptoms associated with the disease. A plethora of animal models have been developed over the years to uncover the molecular alterations that lead to PD development. These models have provided valuable information on neurotransmitter pathways and mechanisms involved. One such a system is the nicotinic cholinergic system. Numerous studies show that nigrostriatal damage affects nicotinic receptor-mediated dopaminergic signaling; therefore therapeutic modulation of the nicotinic cholinergic system may offer a novel approach to manage PD. In fact, there is evidence showing that nicotinic receptor drugs may be useful as neuroprotective agents to prevent Parkinson's disease progression. Additional preclinical studies also show that nicotinic receptor drugs may be beneficial for the treatment of L-dopa induced dyskinesias. Here, we review preclinical findings supporting the idea that nicotinic receptors are valuable therapeutic targets for PD.

Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment.

Methamphetamine use disorder is associated with striatal dopaminergic deficits that have been linked to poor treatment outcomes, identifying these deficits as an important therapeutic target. Exercise attenuates methamphetamine-induced neurochemical damage in the rat brain, and a preliminary observation suggests that exercise increases striatal D2/D3 receptor availability (measured as nondisplaceable binding potential (BPND)) in patients with Parkinson's disease. The goal of this study was to evaluate whether adding an exercise training program to an inpatient behavioral intervention for methamphetamine use disorder reverses deficits in striatal D2/D3 receptors. Participants were adult men and women who met DSM-IV criteria for methamphetamine dependence and were enrolled in a residential facility, where they maintained abstinence from illicit drugs of abuse and received behavioral therapy for their addiction. They were randomized to a group that received 1 h supervised exercise training (n=10) or one that received equal-time health education training (n=9), 3 days/week for 8 weeks. They came to an academic research center for positron emission tomography (PET) using [(18)F]fallypride to determine the effects of the 8-week interventions on striatal D2/D3 receptor BPND. At baseline, striatal D2/D3 BPND did not differ between groups. However, after 8 weeks, participants in the exercise group displayed a significant increase in striatal D2/D3 BPND, whereas those in the education group did not. There were no changes in D2/D3 BPND in extrastriatal regions in either group. These findings suggest that structured exercise training can ameliorate striatal D2/D3 receptor deficits in methamphetamine users, and warrants further evaluation as an adjunctive treatment for stimulant dependence.

Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits.

Repeated methamphetamine (METH) administrations cause persistent dopaminergic deficits resembling aspects of Parkinson's disease. Many METH abusers smoke cigarettes and thus self-administer nicotine; yet few studies have investigated the effects of nicotine on METH-induced dopaminergic deficits. This interaction is of interest because preclinical studies demonstrate that nicotine can be neuroprotective, perhaps owing to effects involving α4β2 and α6β2 nicotinic acetylcholine receptors (nAChRs). This study revealed that oral nicotine exposure beginning in adolescence [postnatal day (PND) 40] through adulthood [PND 96] attenuated METH-induced striatal dopaminergic deficits when METH was administered at PND 89. This protection did not appear to be due to nicotine-induced alterations in METH pharmacokinetics. Short-term (i.e., 21-day) high-dose nicotine exposure also protected when administered from PND 40 to PND 61 (with METH at PND 54), but this protective effect did not persist. Short-term (i.e., 21-day) high-dose nicotine exposure did not protect when administered postadolescence (i.e., beginning at PND 61, with METH at PND 75). However, protection was engendered if the duration of nicotine exposure was extended to 39 days (with METH at PND 93). Autoradiographic analysis revealed that nicotine increased striatal α4β2 expression, as assessed using [(125)I]epibatidine. Both METH and nicotine decreased striatal α6β2 expression, as assessed using [(125)I]α-conotoxin MII. These findings indicate that nicotine protects against METH-induced striatal dopaminergic deficits, perhaps by affecting α4β2 and/or α6β2 expression, and that both age of onset and duration of nicotine exposure affect this protection.

Clinical correlates of raphe serotonergic dysfunction in early Parkinson's disease.

Post-mortem and neuroimaging studies suggest that the serotonergic system, which originates from the brainstem raphe nuclei, is disrupted in Parkinson's disease. This could contribute to the occurrence of non-motor symptoms and tremor, which are only partially explained by dopamine loss. However, the level of involvement of the serotonergic raphe nuclei in early Parkinson's disease is still debated. (123)I-FP-CIT single photon emission computed tomography is a marker of dopamine and serotonin transporter availability. While (123)I-FP-CIT binds primarily to dopamine transporters in the striatum, its binding in the brainstem raphe nuclei reflects serotonin transporter availability. We interrogated baseline single photon emission computed tomography scans of subjects recruited by the Parkinson's Progression Markers Initiative to determine: (i) the integrity of the brainstem raphe nuclei in early Parkinson's disease; and (ii) whether raphe serotonin transporter levels correlate with severity of tremor and symptoms of fatigue, depression, and sleep disturbance. Three hundred and forty-five patients with early drug-naïve Parkinson's disease, 185 healthy controls, and 56 subjects with possible Parkinson's disease without evidence of dopaminergic deficit were included. In the Parkinson's disease cohort, 37 patients had a tremulous, 106 patients had a pure akinetic-rigid, and 202 had a mixed phenotype. Patients with Parkinson's disease had significantly lower serotonin transporter availability in the brainstem raphe nuclei compared to controls (P < 0.01) and subjects without evidence of dopaminergic deficit (P < 0.05). However, only 13% of patients with Parkinson's disease individually had reduced signals. Raphe serotonin transporter availability over the entire Parkinson's disease cohort were associated with rest tremor amplitude (β = -0.106, P < 0.05), rest tremor constancy (β = -0.109, P < 0.05), and index of rest tremor severity (β = -0.104, P < 0.05). The tremulous Parkinson's disease subgroup had significantly lower raphe serotonin transporter availability but less severe striatal dopaminergic deficits compared to akinetic-rigid patients with no resting tremor (P < 0.05). In tremulous patients, raphe serotonin transporter availability was also associated with rest tremor constancy (β = -0.380, P < 0.05) and index of rest tremor severity (β = -0.322, P < 0.05). There was no association between raphe serotonin transporter availability and fatigue, depression, excessive daytime sleepiness, or rapid eye movement sleep behaviour disorder in early Parkinson's disease. We conclude that the raphe nuclei are affected in a subgroup of early drug-naïve Parkinson's disease patients and that reduced raphe serotonin transporter availability is associated with the severity of resting tremor but not non-motor symptoms.

Prior methamphetamine self-administration attenuates the dopaminergic deficits caused by a subsequent methamphetamine exposure

Others and we have reported that prior methamphetamine (METH) exposure attenuates the persistent striatal dopaminergic deficits caused by a subsequent high-dose “binge” METH exposure. The current study investigated intermediate neurochemical changes that may contribute to, or serve to predict, this resistance. Rats self-administered METH or saline for 7 d. On the following day (specifically, 16 h after the conclusion of the final METH self-administration session), rats received a binge exposure of METH or saline (so as to assess the impact of prior METH self-administration), or were sacrificed without a subsequent METH exposure (i.e., to assess the status of the rats at what would have been the initiation of the binge METH treatment). Results revealed that METH self-administration per se decreased striatal dopamine (DA) transporter (DAT) function and DA content, as assessed 16 h after the last self-administration session. Exposure to a binge METH treatment beginning at this 16-h time point decreased DAT function and DA content as assessed 1 h after the binge METH exposure: this effect on DA content (but not DAT function) was attenuated if rats previously self-administered METH. In contrast, 24 h after the binge METH treatment prior METH self-administration: 1) attenuated deficits in DA content, DAT function and vesicular monoamine transporter-2 function; and 2) prevented increases in glial fibrillary acidic protein and DAT complex immunoreactivity. These data suggest that changes 24 h, but not 1 h, after binge METH exposure are predictive of tolerance against the persistence of neurotoxic changes following binge METH exposures.

Cognitive executive impairment and dopaminergic deficits in de novo Parkinson's disease.

Cognitive impairment in Parkinson's disease (PD) is common and does directly impact patients' everyday functioning. However, the underlying mechanisms of early cognitive decline are not known. This study explored the association between striatal dopaminergic deficits and cognitive impairment within a large cohort of early, drug-naïve PD patients and tested the hypothesis that executive dysfunction in PD is associated with striatal dopaminergic depletion. A cross-sectional multicenter cohort of 339 PD patients and 158 healthy controls from the Parkinson's Progression Markers Initiative study was analyzed. Each individual underwent cerebral single-photon emission CT (SPECT) and a standardized neuropsychological assessment with tests of memory as well as visuospatial and executive function. SPECT imaging was performed with [(123) I]FP-CIT, and specific binding ratios in left and right putamen and caudate nucleus were calculated. The association between specific binding ratios, cognitive domain scores, and age was analyzed using Pearson's correlations, partial correlation, and conditional process analysis. A small, but significant, positive association between total striatal dopamine transporter binding and the attention/executive domain was found (r = 0.141; P = 0.009) in PD, but this was not significant after adjusting for age. However, in a moderated mediation model, we found that cognitive executive differences between controls and patients with PD were mediated by an age-moderated striatal dopaminergic deficit. Our findings support the hypothesis that nigrostriatal dopaminergic deficit is associated with executive impairment, but not to memory or visuospatial impairment, in early PD.

Neural correlates of progressive reduction of bradykinesia in de novo Parkinson's disease.

A progressive reduction in the speed and amplitude of repetitive action is an essential component of bradykinesia, which is called sequence effect (SE). Because SE is specific to Parkinson's disease (PD) and is suggested to be associated with motor arrest, its features are of great interest. The aim of this study was, for the first time, to find the neural correlates of SE and to demonstrate whether dopaminergic deficit is correlated with SE. We enrolled 12 patients with de novo PD at a tertiary referral hospital. Correlations between SE severity and alterations in gray and white matter were studied. The association between severity of the SE and striatal dopaminergic deficits was also analyzed. There was a significant negative correlation between the volumetric changes in the anterior cingulate cortex (ACC) and the inferior semilunar lobule of the cerebellum and the degree of SE. There was a significant correlation between the long association fibers (the superior longitudinal fasciculus, the uncinate fasciculus, and the inferior fronto-occipital fasciculus) connecting the frontal lobes to the temporal, parietal, and occipital lobes and SE. There was a significant negative correlation between SE in the more affected hand and the caudate dopamine transporter binding in the more affected hemisphere. Our results suggest that the ACC and the cerebellum (inferior semilunar lobule) are associated with the severity of SE. Taken together with DTI findings, the present study proposes that ACC may have an important role. Our data show that the caudate dopaminergic activity may be related to SE.

Impact of regional striatal dopaminergic function on kinematic parameters of Parkinson's disease.

Among the cardinal parkinsonian motor deficits, the severity of bradykinesia correlates with striatal dopamine loss. However, the impact of regional striatal dopamine loss on specific components of bradykinesia remains unknown. Using gyroscopes, we measured the amplitude, speed, and frequency of finger tapping in 24 untreated patients with Parkinson's disease (PD) and 28 healthy controls. Using positron emission tomography (PET) studies and [(18)F]-N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane (FP-CIT) in PD patients, we investigated the relationship between the mean values, variability and decrements of various kinematic parameters of finger tapping on one side (e.g. the mean, variability and decrement) and contralateral striatal FP-CIT binding. Compared with controls, PD patients had reduced amplitudes and speeds of tapping and showed greater decrement in those parameters. PD patients also exhibited greater irregularity in amplitude, speed, and frequency. Putaminal FP-CIT uptake levels correlated with the mean speed and amplitude, and caudate uptake levels correlated with mean amplitude. The variability of amplitude and speed correlated only with the caudate uptake levels. Neither caudate nor putaminal uptake correlated with frequency-related parameters or decrement in amplitude or speed. Reduced amplitude and speed of repetitive movement may be related to striatal dopaminergic deficit. Dopaminergic action in the caudate nucleus is required to maintain consistency of amplitude and speed. Although decrement of amplitude and speed is known to be specific for PD, we found that it did not mirror the degree of striatal dopamine depletion.

Is ioflupane I123 injection diagnostically effective in patients with movement disorders and dementia? Pooled analysis of four clinical trials

ObjectivesTo pool clinical trials of similar design to assess overall sensitivity and specificity of ioflupane I123 injection (DaTSCAN or ioflupane (123I)) to detect or exclude a striatal dopaminergic deficit disorder...

Individual-reader diagnostic performance and between-reader agreement in assessment of subjects with Parkinsonian syndrome or dementia using 123I-ioflupane injection (DaTscan) imaging.

Establishing an early, accurate diagnosis is fundamental for appropriate clinical management of patients with movement disorders or dementia. Ioflupane (123)I Injection (DaTscan, (123)I-ioflupane) is an important adjunct to support the clinical diagnosis. Understanding individual-reader diagnostic performance of (123)I-ioflupane in a variety of clinical scenarios is essential. Sensitivity, specificity, interreader, and intrareader data from 5 multicenter clinical studies were reviewed. The different study designs offered an assortment of variables to assess the effects on the diagnostic performance of (123)I-ioflupane: on-site versus 3-5 blinded image readers, number of image evaluations, early/uncertain versus late/confirmed clinical diagnosis as reference standard, and subjects with movement disorders versus dementia. Eight hundred eighteen subjects had individual-reader efficacy data available for analysis. In general, sensitivity and specificity were high and comparable between on-site versus blinded independent readers. In subjects with dementia, when the clinical diagnosis was made at month 12 versus baseline, specificity improved from 77.4%-91.2% to 81.6%-95.0%. In subjects with movement disorders, this effect was observed to an even greater extent, when diagnostic performance using month-18 diagnosis as a reference standard (sensitivity, 67.0%-73.7%; specificity, 75.0%-83.3%) was compared versus month-36 diagnosis (77.5%-80.3% and 90.3%-96.8%, respectively). Diagnostic performance was similar in subjects with dementia (74.4%-89.9% and 77.4%-95.0%, respectively) and subjects with movement disorders (67.0%-97.9% and 71.4%-98.4%, respectively). In most of the comparisons, between-reader agreement was very good (almost perfect), with κ ranging from 0.81 to 1.00. Within-reader agreement, measured in 1 study, was 100% for 3 blinded readers. Individual-reader diagnostic performance, as assessed by measuring sensitivity and specificity of (123)I-ioflupane to detect the presence or absence of striatal dopaminergic deficit, using the clinical diagnosis as a reference standard, was high in subjects with either movement disorders or dementia and was similar in on-site readers versus blinded analyses. Between- and within-reader agreements were very good (almost perfect). Longer follow-up between imaging and clinical diagnosis improved the diagnostic accuracy, most likely due to improvement in the clinical diagnosis reference standard, rather than changes in reader accuracy.

The PD-associated alpha-synuclein promoter Rep1 allele 2 shows diminished frequency in restless legs syndrome.

Gain-of-function mutations of alpha-synuclein (SNCA) are known to trigger Parkinson's disease (PD) with striatal dopaminergic deficits and a reduction of spontaneous movements. The longest size variant (allele 2) of the complex microsatellite repeat Rep1 within the SNCA gene promoter is known to confer a PD risk. We now observed this Rep1 allele 2 to show significantly decreased frequency in restless legs syndrome (RLS) in a genotyping study of 258 patients versus 235 healthy controls from Germany. Given that RLS is a disease with increased spontaneous movements and with increased striatal dopamine signaling, these novel data appear plausible. The scarcity of this alpha-synuclein gain-of-function variant in RLS might suggest that a low alpha-synuclein function via the SNARE complex in presynaptic vesicle release and neurotransmission of the striatum contributes to RLS pathogenesis.

Dietary supplementation with resveratrol protects against striatal dopaminergic deficits produced by in utero LPS exposure

The purpose of this study was to determine the effect of dietary supplementation with the anti-inflammatory compound resveratrol in pregnant dams on lipopolysaccharide (LPS)-induced dopaminergic deficits in pups exposed to LPS in utero. Gravid female rats were fed with a resveratrol-enriched diet during gestational days 3–22.5 (E3–E22.5) and received an intraperitoneal (i.p.) injection of 1mg/kg LPS at E10.5. The striata were isolated from the pups at postnatal days 10 (P10) and P21. LPS-induced dopaminergic deficits were noted at P21, but not P10. These DA deficits at P21 were exhibited by a loss of DA and DA metabolite [3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] levels and tyrosine hydroxylase (TH) expression in the striatum. The LPS-induced loss of DA, DA metabolites, and TH expression were attenuated in the striata of pups from the dams fed with the resveratrol-supplemented diet. These data suggest that a resveratrol-supplemented diet may restore homeostasis of the striatal DA neuronal system following disruption by LPS.

Stroke Literature Synopses: Basic Science

HomeStrokeVol. 45, No. 2Stroke Literature Synopses: Basic Science Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBStroke Literature Synopses: Basic Science Originally published2 Jan 2014https://doi.org/10.1161/STROKEAHA.113.004069Stroke. 2014;45:e13Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2014: Previous Version 1 IntroductionCurrently, there are no clinically effective neuro protectants not only for stroke, but also more broadly across all central nervous system disorders. Fundamentally, it is now recognized that regardless of the specific disorder, there may be unifying mechanisms that are common to protecting neurons against injury and disease. Three recent studies suggest novel therapeutic approaches for neuroprotection in animal models of neurodegeneration. Further investigation of these pathways may eventually yield ideas and targets with relevance for stroke as well.Lee et al (Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. Nat Neurosci. 2013;16:1392–1400) reported that aminoacyl-tRNA synthetase complex interacting multifunctional protein-2 (AIMP2) causes a selective, age-dependent, progressive loss of dopaminergic neurons. AIMP2 is a parkin substrate that is present in Lewy body inclusions of the Parkinson disease substantia nigra. Mutations in the ubiquitin E3 ligase PARKIN are an important cause of familial Parkinson disease, and AIMP2 is a strong candidate as a pathogenic parkin substrate. AIMP2 levels are known to be elevated in both patients with Parkinson disease and animal models. This study prepared a novel transgenic mouse line with AIMP2 overexpression and showed that AIMP2 accumulation leads to an age-dependent degeneration of dopaminergic neurons, which eventually cause Parkinson disease–like symptoms such as striatal dopaminergic deficits and dysfunctional motor coordination. As an underlying mechanism in AIMP2-induced doparminergic neuronal damage, the authors demonstrated that AIMP2 activates poly ADP ribose polymerase1 (PARP1), which is one of the major molecules for apoptosis. Importantly, knockout or inhibition of PARP1 prevented the AIMP2-mediated dopaminergic neuronal death. Therefore, brain-permeable PARP inhibitors could be effective for neuroprotection in some neurodegenerative diseases.Mechanisms for neuronal death may depend on neuronal cell types. Saxena et al (Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival. Neuron. 2013;80:80–96) examined endogenous neuroprotection mechanisms in motoneurons using transgenic mice with mutant superoxide dismutase1 (SOD1), which are widely used as a mouse model of familial amyotropic lateral sclerosis. In early postnatal stages (postnatal day ≈7), a subpopulation of α-motoneurons exhibited misfolded SOD1 accumulation. The vulnerability of motoneurons may be related to their lower excitability because enhancing motoneuron excitability promoted the viability of motoneurons and reversed the misfolded SOD accumulation. On the contrary, direct pharmacological inhibition of excitability in motoneurons enhanced misfolded SOD1 accumulation and endoplasmic reticulum stress. In addition, when the mammalian target of rapamycin (mTOR) inhibitor rapamycin was chronically treated, the familial amyotropic lateral sclerosis transgenic mice showed the disease progression such as misfolded SOD accumulation and increased endoplasmic reticulum stress in the vulnerable motoneurons. Taken together, these results suggest that excitability signaling leading to mTOR activation would be a critical mechanism for neuroprotection in motoneurons in the amyotrophic lateral sclerosis (ALS) model mice. Thus, endogenous neuroprotection pathways may be valuable therapeutic targets for neuroprotection in central nervous system diseases.When we seek neuroprotection, we may also need to pay attention to neuronal axons that are enwrapped by myelin sheath. Laterza et al (iPSC-derived neural precursors exert a neuroprotective role in immune-mediated demyelination via the secretion of LIF. Nat Commun. 2013;4:2597) reveal novel mechanisms by which transplanted mouse induced pluripotent stem cell (iPSC)-derived neural stem/precursor cells (miPSC-NPCs) exert the neuroprotective effect in a mouse model of multiple sclerosis. Compared with sham-treated multiple sclerosis mice, miPSC-NPC–treated multiple sclerosis mice promoted the functional recovery and exhibited a better preservation of myelin/axonal integrity. Because the transplanted miPSC-NPCs persisted undifferentiated within perivascular infiltrates, the neuroprotective effects were at least partly mediated via the secretion of a specific neurotrophin by the miPSCs-NPCs. In vitro and in vivo examinations demonstrated that miPSC-NPC–derived leukemia inhibitory factor promoted remyelination. iPSCs have opened a new avenue of translational research in the cell transplantation approaches, and this study expands the therapeutic potential of iPSCs for neuroprotection in myelin disorder diseases.Although clinical trials of neuroprotectants have failed in our stroke field to date, the search for effective drugs to protect neurons must continue. In this regard, the findings introduced above should be helpful because they provide a deeper understanding of fundamental mechanisms that may eventually lead to new ways to achieve neuroprotection in patients with stroke. Previous Back to top Next FiguresReferencesRelatedDetails February 2014Vol 45, Issue 2 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.113.004069 Originally publishedJanuary 2, 2014 PDF download Advertisement SubjectsNeuroprotectants

Thalamic cholinergic innervation and postural sensory integration function in Parkinson’s disease

The pathophysiology of postural instability in Parkinson's disease remains poorly understood. Normal postural function depends in part on the ability of the postural control system to integrate visual, proprioceptive, and vestibular sensory information. Degeneration of cholinergic neurons in the brainstem pedunculopontine nucleus complex and their thalamic efferent terminals has been implicated in postural control deficits in Parkinson's disease. Our aim was to investigate the relationship of cholinergic terminal loss in thalamus and cortex, and nigrostriatal dopaminergic denervation, on postural sensory integration function in Parkinson's disease. We studied 124 subjects with Parkinson's disease (32 female/92 male; 65.5 ± 7.4 years old; 6.0 ± 4.2 years motor disease duration; modified Hoehn and Yahr mean stage 2.4 ± 0.5) and 25 control subjects (10 female/15 male, 66.8 ± 10.1 years old). All subjects underwent (11)C-dihydrotetrabenazine vesicular monoaminergic transporter type 2 and (11)C-methylpiperidin-4-yl propionate acetylcholinesterase positron emission tomography and the sensory organization test balance platform protocol. Measures of dopaminergic and cholinergic terminal integrity were obtained, i.e. striatal vesicular monoaminergic transporter type 2 binding (distribution volume ratio) and thalamic and cortical acetylcholinesterase hydrolysis rate per minute (k3), respectively. Total centre of pressure excursion (speed), a measure of total sway, and sway variability were determined for individual sensory organization test conditions. Based on normative data, principal component analysis was performed to reduce postural sensory organization functions to robust factors for regression analysis with the dopaminergic and cholinergic terminal data. Factor analysis demonstrated two factors with eigenvalues >2 that explained 52.2% of the variance, mainly reflecting postural sway during sensory organization test Conditions 1-3 and 5, respectively. Regression analysis of the Conditions 1-3 postural sway-related factor [R(2)adj = 0.123, F(5,109) = 4.2, P = 0.002] showed that decreased thalamic cholinergic innervation was associated with increased centre of pressure sway speed (β = -0.389, t = -3.4, P = 0.001) while controlling for covariate effects of cognitive capacity and parkinsonian motor impairments. There was no significant effect of cortical cholinergic terminal deficits or striatal dopaminergic terminal deficits. This effect could only be found for the subjects with Parkinson's disease. We conclude that postural sensory integration function of subjects with Parkinson's disease is modulated by pedunculopontine nucleus-thalamic but not cortical cholinergic innervation. Impaired integrity of pedunculopontine nucleus cholinergic neurons and their thalamic efferents play a role in postural control in patients with Parkinson's disease, possibly by participating in integration of multimodal sensory input information.

Depressive symptoms in Parkinson's disease are related to reduced [123I]FP-CIT binding in the caudate nucleus

BackgroundDepression is a common neuropsychiatric symptom in Parkinson's disease (PD). In previous research, PD-related depression was associated with striatal dopaminergic deficits, presumably due to degeneration of brainstem dopaminergic projections. Segregated...