Neuronal Loss Is Greater in the Locus Coeruleus Than Nucleus Basalis and Substantia Nigra in Alzheimer and Parkinson Diseases

Zarow, Chris; Lyness, Scott A.; Mortimer, James A.; Chui, Helena C.

doi:10.1001/archneur.60.3.337

Cited by 873 publications

(690 citation statements)

References 34 publications

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“…However, studies of post-mortem PD brains have shown that not only DA neurons in the SN but also noradrenaline (NA) neurons in the locus coeruleus (LC) degenerate, and that NA neurodegeneration may be as profound, and also precede, degeneration of midbrain DA neurons (German et al, 1992;Patt and Gerhard, 1993;Zarow et al, 2003). The early involvement of the NA system is also in line with the caudal-to-rostral disease progression predicted by the model proposed by Braak et al (Braak et al, 2003;Hawkes et al, 2007Hawkes et al, , 2009).…”

Section: Introductionmentioning

confidence: 73%

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

Shin

Rogers

Devoto

et al. 2014

Experimental Neurology

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Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, studies of post-mortem PD brains have shown that not only DA neurons but also the noradrenergic (NA) neurons in the locus coeruleus degenerate, and that the NA neurodegeneration may be as profound, and also precede degeneration of the midbrain DA neurons. Previous studies in animal models of PD have suggested that loss of forebrain NA will add to the development of motor symptoms in animals with lesions of the nigrostriatal DA neurons, but the results obtained in rodents have been inconclusive due to the shortcomings of the toxin, DSP-4, used to lesion the NA projections. Here, we have developed an alternative double-lesion paradigm using injections of 6-OHDA into striatum in combination with intraventricular injections of a powerful NA immunotoxin, anti-DBH-Saporin, to eliminate the NA neurons in the brain.Animals with combined DA and NA lesions were more prone to develop L-DOPAinduced dyskinesia, even at low L-DOPA doses, and they performed significantly worse in tests of reflexive and skilled paw use, the stepping and staircase tests, compared to DA-only lesioned rats. Post-mortem analysis revealed that NA depletion did not affect the degree of DA depletion, or the loss of tyrosine hydroxylase-positive innervation in the striatum. Cell loss in the substantia nigra was similar in both single and double lesioned animals, showing that the worsening effect was not due to increased loss of nigral DA neurons. The results show that damage to the NA neurons in the central nervous system contributes to the development of motor impairments and the appearance of L-DOPAinduced dyskinesia in 6-OHDA lesioned rats, and provide support for the view that the development of motor symptoms and dyskinetic side effects in PD patients reflects the combined loss of midbrain DA neurons and NA neurons.3

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Section: Introductionmentioning

confidence: 73%

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

Shin

Rogers

Devoto

et al. 2014

Experimental Neurology

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“…Indeed, drugs that affect these neuromodulators substantially reduce the benefits of VNS therapy in tinnitus patients [45], indicating that these neuromodulatory pathways are necessary for the effects of VNS. Several diseases affect cell number and function in these neuromodulatory systems, including Alzheimer disease, PD, chronic alcoholism, Down syndrome, TBI, and PTSD [118][119][120][121][122][123][124][125][126]. Comorbidity with these and other diseases that impair neuromodulatory function may limit the effects of VNS.…”

Section: Challenges For Translating Vns Therapies Into Clinical Practmentioning

confidence: 99%

Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation

Hays

2016

Neurotherapeutics

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Pathological neural activity could be treated by directing specific plasticity to renormalize circuits and restore function. Rehabilitative therapies aim to promote adaptive circuit changes after neurological disease or injury, but insufficient or maladaptive plasticity often prevents a full recovery. The development of adjunctive strategies that broadly support plasticity to facilitate the benefits of rehabilitative interventions has the potential to improve treatment of a wide range of neurological disorders. Recently, stimulation of the vagus nerve in conjunction with rehabilitation has emerged as one such potential targeted plasticity therapy. Vagus nerve stimulation (VNS) drives activation of neuromodulatory nuclei that are associated with plasticity, including the cholinergic basal forebrain and the noradrenergic locus coeruleus. Repeatedly pairing brief bursts of VNS sensory or motor events drives robust, event-specific plasticity in neural circuits. Animal models of chronic tinnitus, ischemic stroke, intracerebral hemorrhage, traumatic brain injury, and post-traumatic stress disorder benefit from delivery of VNS paired with successful trials during rehabilitative training. Moreover, mounting evidence from pilot clinical trials provides an initial indication that VNS-based targeted plasticity therapies may be effective in patients with neurological diseases and injuries. Here, I provide a discussion of the current uses and potential future applications of VNS-based targeted plasticity therapies in animal models and patients, and outline challenges for clinical implementation.

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“…Although neuritic plaques and their amyloid components continue to play a critical role in the diagnosis of Alzheimer's disease (AD), semi-quantitative studies in groups of normalaged and AD patients have reported that these so-called neuropathological markers of AD also occur to varying degrees in cortical tissue during normal aging, and that their accumulation does not directly correlate with the progression of dementia (Mirra et al 1993;McKeel et al 2004;Tiraboschi et al 2004). Stereological and neurochemical studies of brain tissue from patients with AD have confirmed widespread astrocytosis and microgliosis in cortical brain regions and significant reductions in neurotransmitter-specific subcortical nuclei, including the locus coeruleus (LC) and dorsal raphe (DR), and diminished concentrations in their cortical projections of corresponding monoamine neurotransmitters, norepinephrine (NE) and 5-hydroxytrptamine (5-HT); in contrast, these parameters remain relatively stable in brains of persons that undergo normal (non-demented) brain aging (Aletrino et al 1992;Mouton et al 1994;Storga et al 1996;Zarow et al 2003;Tuppo and Arias 2005). The strongest correlations with dementia severity have been reported in the loss of cortical volume (atrophy), observed by either ante-mortem or post-mortem analyses, and the reduction in cortical synapses (de la Monte 1989;DeKosky and Scheff 1990;Terry et al 1991;Convit et al 1993;Jobst et al 1994;Stout et al 1996;Mouton et al 1998;Zarow et al 2003;de Leon et al 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Stereological and neurochemical studies of brain tissue from patients with AD have confirmed widespread astrocytosis and microgliosis in cortical brain regions and significant reductions in neurotransmitter-specific subcortical nuclei, including the locus coeruleus (LC) and dorsal raphe (DR), and diminished concentrations in their cortical projections of corresponding monoamine neurotransmitters, norepinephrine (NE) and 5-hydroxytrptamine (5-HT); in contrast, these parameters remain relatively stable in brains of persons that undergo normal (non-demented) brain aging (Aletrino et al 1992;Mouton et al 1994;Storga et al 1996;Zarow et al 2003;Tuppo and Arias 2005). The strongest correlations with dementia severity have been reported in the loss of cortical volume (atrophy), observed by either ante-mortem or post-mortem analyses, and the reduction in cortical synapses (de la Monte 1989;DeKosky and Scheff 1990;Terry et al 1991;Convit et al 1993;Jobst et al 1994;Stout et al 1996;Mouton et al 1998;Zarow et al 2003;de Leon et al 2004). Thus, the evidence to date indicates that, while the diagnosis of AD depends heavily on the presence of amyloid plaques in neocortical brain regions, the progression of AD dementia appears to correlate more closely with degeneration of subcortical neurotransmitter systems that project to cortex, cortical synapse loss, and reduction of cortical volumes.…”

Section: Introductionmentioning

confidence: 99%

Neuropathological quantification of dtg APP/PS1: neuroimaging, stereology, and biochemistry

Manaye

Wang

O’Neil

et al. 2007

AGE

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Murine models that mimic the neuropathology of Alzheimer's disease (AD) have the potential to provide insight into the pathogenesis of the disease and lead to new strategies for the therapeutic management of afflicted patients. We used magnetic resonance imaging (MRI), design-based stereology, and high performance liquid chromatography (HPLC) to assess the age-related neuropathology in double transgenic mice that overexpress two AD-related proteins-amyloid precursor protein (APP) and presenilin 1 (PS1)-and age-and gender-matched wild-type (WT) controls. In mice ranging in age from 4-28 months, total volumes of the hippocampal formation (V HF ) and whole brain (V brain ) were quantified by the Cavalieri-point counting method on a systematic-random sample of coronal T2-weighted MRI images; the same stereological methods were used to quantify V HF and V brain after perfusion and histological processing. To assess changes in ADtype beta-amyloid (Aβ) plaques, sections from the hippocampal formation and amylgdaloid complex of mice aged 5, 12, and 15 months were stained by Congo Red histochemistry. In aged mice with large numbers of amyloid plaques, systematic-random samples of sections were stained by GFAP immunocytochemistry to assess gender and genotype effects on total numbers of astrocytes. In addition, levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and 5-HT metabolites were assayed by HPLC in fresh-frozen samples from neocortex, striatum, hippocampus, and brainstem. We confirmed age-related increases in amyloid plaques, beginning with a few plaques at 5 months of age and increasing densities by AGE (2007) 12 and 15 months. At 15 months of age, there were robust genotype effects, but no gender effects, on GFAP-immunopositive astrocytes in the amygdaloid complex and hippocampus. There were no effects on monoamine levels in all brain regions examined, and no volume changes in hippocampal formation or whole brain as quantified on either neuroimages or tissue sections. Strong correlations were present between volume estimates from MRI images and histological sections, with about 85% reduction in mean V HF or mean V brain between MRI and processed histological sections. In summary, these findings show that the double transgenic expression of AD-type mutations is associated with age-related increases in amyloid plaques and astrocytosis; however, this model does not recapitulate the cortical atrophy or neurochemical changes that are characteristic of AD.29:87-96 DOI 10.1007/s11357-007-9035-

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Neuronal Loss Is Greater in the Locus Coeruleus Than Nucleus Basalis and Substantia Nigra in Alzheimer and Parkinson Diseases

Cited by 873 publications

References 34 publications

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease

Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation

Neuropathological quantification of dtg APP/PS1: neuroimaging, stereology, and biochemistry

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