Noradrenergic changes, aggressive behavior, and cognition in patients with dementia

Matthews, Kim L.; Chen, Christopher P.L.-H.; Esiri, Margaret M.; Keene, Judith; Minger, Stephen; Francis, Paul T.

doi:10.1016/s0006-3223(01)01235-5

Cited by 190 publications

(146 citation statements)

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“…Previous research has not suggested an association between Lewy bodies and nigral neuronal loss in Parkinson disease, 24,25 but studies of individuals with and without dementia have found tangles to be associated with lower neuronal density in the dorsal raphe nucleus 26 and medial temporal lobe. 27 Most prior studies have included a substantial proportion of persons with severe dementia, 23,28 but only 6.7% of individuals in the present study had a Mini-Mental State Examination score ,10 at the last evaluation before death. The absence of a tangle-neuron association, therefore, might indicate that substantial loss of neurons in brainstem aminergic nuclei mainly occurs late in the course of AD as reported for the hippocampus and entorhinal cortex.…”

Section: Figurementioning

confidence: 68%

“…Among persons with dementia, having few locus ceruleus neurons has been associated with lower level of cognition in some studies 21,22 but not others. 23 We are not aware of previous studies of locus ceruleus neurons and change in cognition over time. Thus, the present results extend previous research by showing that neuronal density in these brainstem nuclei is related to the primary clinical manifestation of AD, accelerated cognitive decline, and that it is noradrenergic neurons in the locus ceruleus that are primarily responsible for the association.…”

Section: Figurementioning

confidence: 99%

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Neural reserve, neuronal density in the locus ceruleus, and cognitive decline

et al. 2013

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Objective: To test the hypothesis that higher neuronal density in brainstem aminergic nuclei contributes to neural reserve.Methods: Participants are 165 individuals from the Rush Memory and Aging Project, a longitudinal clinical-pathologic cohort study. They completed a mean of 5.8 years of annual evaluations that included a battery of 19 cognitive tests from which a previously established composite measure of global cognition was derived. Upon death, they had a brain autopsy and uniform neuropathologic examination that provided estimates of the density of aminergic neurons in the locus ceruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area plus summary measures of neuronal neurofibrillary tangles and Lewy bodies from these nuclei and medial temporal lobe and neocortex.Results: Neuronal densities in each nucleus were approximately normally distributed. In separate analyses, higher neuronal density in each nucleus except the ventral tegmental area was associated with slower rate of cognitive decline, but when modeled together only locus ceruleus neuronal density was related to cognitive decline (estimate 5 0.003, SE 5 0.001, p , 0.001). Higher densities of tangles and Lewy bodies in these brainstem nuclei were associated with faster cognitive decline even after controlling for pathologic burden elsewhere in the brain. Locus ceruleus neuronal density, brainstem tangles, and brainstem Lewy bodies had independent associations with rate of cognitive decline. In addition, at higher levels of locus ceruleus neuronal density, the association of Lewy bodies with cognitive decline was diminished. ) or their components (synapses 8,9 ) in key locations. This approach allows collection of neuronal and pathologic data from the same brain regions, facilitating examination of their conjoint correlations with cognition. ConclusionThe present study examines the associations among neuronal density, neurodegenerative lesions, and change in cognitive function. We assessed neuronal density in brainstem aminergic nuclei (i.e., locus ceruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area) because these nuclei support multiple cognitive processes, synthesize important monoamines that function as neurotransmitters and neuromodulators, are therapeutic targets for cognitive enhancement, 10 and bear a disproportionate burden of age-related neurodegeneration. 11,12 Participants from the Rush Memory and Aging Project had annual cognitive testing for a mean of 5.8 years, died, and underwent a neuropathologic examination that yielded neuronal counts for each brainstem nucleus From the Rush Alzheimer's Disease

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Section: Figurementioning

confidence: 68%

Section: Figurementioning

confidence: 99%

Neural reserve, neuronal density in the locus ceruleus, and cognitive decline

et al. 2013

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“…Discussion LC degeneration and loss of LC-derived axons are associated with decreased NE levels in target forebrain regions in AD patients (4,13,14). Although these studies have assessed the loss of LC-noradrenergic neurons, it remains unclear when LC cell death starts and whether this structural degeneration is preceded by a significant period of dysfunction of noradrenergic LC neurons.…”

Section: Ne Depletion Decreases Microglial Phagocytosis and Recruitmementioning

confidence: 99%

“…Of particular relevance, several studies show that AD patients present with a prominent loss of LC cells, reaching 70% within the rostral nucleus and causing reduction of cortical and limbic NE levels (4). The drop in NE concentration tightly correlates with the progression and extent of memory dysfunction and cognitive impairment.…”

mentioning

confidence: 99%

Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine

Heneka

Nadrigny

Regen

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

444

420

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Locus ceruleus (LC)-supplied norepinephrine (NE) suppresses neuroinflammation in the brain. To elucidate the effect of LC degeneration and subsequent NE deficiency on Alzheimer's disease pathology, we evaluated NE effects on microglial key functions. NE stimulation of mouse microglia suppressed Aβ-induced cytokine and chemokine production and increased microglial migration and phagocytosis of Aβ. Induced degeneration of the locus ceruleus increased expression of inflammatory mediators in APP-transgenic mice and resulted in elevated Aβ deposition. In vivo laser microscopy confirmed a reduced recruitment of microglia to Aβ plaque sites and impaired microglial Aβ phagocytosis in NE-depleted APP-transgenic mice. Supplying the mice the norepinephrine precursor L-threo-DOPS restored microglial functions in NE-depleted mice. This indicates that decrease of NE in locus ceruleus projection areas facilitates the inflammatory reaction of microglial cells in AD and impairs microglial migration and phagocytosis, thereby contributing to reduced Aβ clearance. Consequently, therapies targeting microglial phagocytosis should be tested under NE depletion.neuroinflammation | amyloid beta | neurodegeneration | phagocytosis A lzheimer's disease (AD) is characterized by neocortical and hippocampal atrophy due to neuronal loss, the deposition of Aβ peptides, and the formation of neurofibrillar tangles. In addition, there is a progressive degeneration of cholinergic nuclei in the basal forebrain and of noradrenergic nuclei in the brainstem, most importantly the locus ceruleus (LC). This nucleus is the major source of norepinephrine (NE) supply in the mammalian brain. The LC provides the neurotransmitter via an extensive network of neuronal projections to all major brain regions. These regions include the neocortex and hippocampus, the seat of cognitive functions, learning, and memory.Research dating back to the 1960s implicated LC degeneration in the pathogenesis of AD (1-3). Of particular relevance, several studies show that AD patients present with a prominent loss of LC cells, reaching 70% within the rostral nucleus and causing reduction of cortical and limbic NE levels (4). The drop in NE concentration tightly correlates with the progression and extent of memory dysfunction and cognitive impairment. Degeneration of LC neurons has been observed in patients exhibiting "mild cognitive impairment" (MCI) (5), an early form of AD, with 80% of MCI patients eventually succumbing to full AD (6).Degeneration of LC neurons results in progressive loss of two different types of axons, those with either conventional synaptic contacts or varicosities. Varicosities are believed to release transmitter extrasynaptically into the microenvironment, where it may act on surrounding neurons, glial cells, and blood vessels (7). Locally diffusing NE is thought to execute additional functions apart from its role as a classical neurotransmitter. Indeed, NE negatively regulates transcription of inflammatory genes in astrocytes and microglia (8), both expressi...

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“…The LC serves as main source of noradrenergic innervation to various cortical areas, including the hippocampus, entorhinal, and frontal cortex. LC degeneration and the subsequent loss of arising axons result in decreased noradrenaline (NA) levels in respective brain regions of AD patients (Adolfsson et al, 1979;Mann et al, 1980;Matthews et al, 2002). The reduction of LC neurons correlates with amyloid-␤ (A␤) plaques, neurofibrillary tangles, and the severity of dementia (Bondareff et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Locus Ceruleus Degeneration Promotes Alzheimer Pathogenesis in Amyloid Precursor Protein 23 Transgenic Mice

et al. 2006

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Locus ceruleus (LC) degeneration and loss of cortical noradrenergic innervation occur early in Alzheimer's disease (AD). Although this has been known for several decades, the contribution of LC degeneration to AD pathogenesis remains unclear. We induced LC degeneration with N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4) in amyloid precursor protein 23 (APP23) transgenic mice with a low amyloid load. Then 6 months later the LC projection areas showed a robust elevation of glial inflammation along with augmented amyloid plaque deposits. Moreover, neurodegeneration and neuronal loss significantly increased. Importantly, the paraventricular thalamus, a nonprojection area, remained unaffected. Radial arm maze and social partner recognition tests revealed increased memory deficits while high-resolution magnetic resonance imaging-guided micro-positron emission tomography demonstrated reduced cerebral glucose metabolism, disturbed neuronal integrity, and attenuated acetylcholinesterase activity. Nontransgenic mice with LC degeneration were devoid of these alterations. Our data demonstrate that the degeneration of LC affects morphology, metabolism, and function of amyloid plaque-containing higher brain regions in APP23 mice. We postulate that LC degeneration substantially contributes to AD development.

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Noradrenergic changes, aggressive behavior, and cognition in patients with dementia

Cited by 190 publications

References 53 publications

Neural reserve, neuronal density in the locus ceruleus, and cognitive decline

Neural reserve, neuronal density in the locus ceruleus, and cognitive decline

Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine

Locus Ceruleus Degeneration Promotes Alzheimer Pathogenesis in Amyloid Precursor Protein 23 Transgenic Mice

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