Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer's disease
Introduction
Alzheimer's disease (AD) leads to severe cognitive and behavioral impairments that compromise independent daily activities. Neurofibrillary tangles (NFTs) and β-amyloid plaques in cortical and subcortical areas are its prominent histopathological markers. Other significant features include neuronal death, synaptic loss and depletion of transmitters such as acetylcholine, serotonin and noradrenaline (NA) [15]. The loss of neurotransmitters has attracted a great deal of attention because it is the one aspect of the disease most amenable to pharmacological intervention. Determining the time course of transmitter-specific pathologies helps to differentiate the degenerative changes that are part of the initial pathogenetic cascade from those that may reflect end-stage events. This is an important distinction since changes that can be traced to the early and prodromal stages of the disease become potential targets for therapies aimed at disease prevention. Addressing this question requires postmortem examination of subjects who have had longitudinal neuropsychological characterization until shortly before death.
We recently conducted such an investigation on cholinergic pathways in a sample of 12 rigorously characterized subjects. We found that cytoskeletal abnormalities in the nucleus basalis (NB), the origin of cholinergic innervation of the cerebral cortex, begin during the course of normal aging and that they become significantly more prominent at a prodromal stage of the disease known as mild cognitive impairment or MCI. We also determined that the extent of cytopathology in the NB was significantly correlated with performance on a delayed memory test, suggesting that pathological alterations in cortical cholinergic pathways may contribute to the declining memory performance seen in the course of the age-MCI-AD continuum [26].
The present study aimed to determine whether a similar conclusion can be reached in the case of the noradrenergic projections originating in the nucleus locus coeruleus (LC). This nucleus displays severe cytopathology in advanced stages of AD, leading to a prominent loss of noradrenergic markers in the cerebral cortex [3], [18], [22], [46]. However, the status of the LC at the earlier stages of the aging-MCI-AD continuum has yet to be investigated in a neuropsychologically well characterized sample of individuals.
The LC is the primary source of cortical, thalamic, cerebellar, brain stem and spinal cord NA. Its ascending projections branch extensively and innervate all parts of the cerebral cortex [14], [27], [35]. Investigations in several animal models have demonstrated that the activity of LC neurons and the resultant release of NA influence attention, arousal and memory [39]. This noradrenergic innervation is thought to optimize the signal-to-noise ratio at the stage of information processing and to influence response selection at the stage of decision making [8], [11]. Increasing LC neuronal activity mediates changes from EEG synchronization to low voltage fast activity, from slow wave sleep to REM, and from behavioral drowsiness to vigilance. In humans, clinical experience suggests that a deficiency of cortical monoamines, including NA, promotes symptoms of depression [7], [45], [46]. A dysfunction of LC neurons and its resultant effects on cortical NA could therefore contribute to the deterioration of mood as well as cognition in AD.
Section snippets
Participants
Postmortem brainstem tissue was obtained from participants who enlisted in a longitudinal study at the University of Miami and who were cognitively normal at the time of entry. All subjects agreed to annual neuropsychological testing and consented to brain donation. From the study's data bank, we identified all subjects who had converted from normalcy to impairment and who had at least two full neuropsychological tests within the enrolment period. The criteria also required that one of these
Neuropsychological subject characterizations
Table 1, Table 2, respectively, provide a summary of the pathological and neuropsychological characteristics of the cognitively normal (CN) and cognitively impaired (CI) subjects. In all five cases with cognitive impairment, there was indication of a decline in cognitive performance so that the approximate the time of conversion from normal to MCI or from MCI to early AD could be determined. Examples of CN and CI neuropsychological profiles are depicted in Fig. 1.
Neuropathology
When examined with the stains
Discussion
Pathology in the LC and loss of cortical noradrenergic markers in AD have been reported previously [15]. For example, Zweig and colleagues reported significant neuronal loss and NFTs in the LC of patients with AD [46]. Furthermore, Mann et al. found a correlation between LC atrophy and frequency of NFTs in the cortex [23] while Bondareff et al. reported a positive correlation of NFTs with the duration and severity of the dementia [4]. In a study of 47 autopsied specimens from subjects with AD,
Note added in proof
Heneka et al. reported that experimentally induced LC degeneration promoted amyloid plaque deposition and neuronal loss in an APP23 transgenic mouse model of AD, leading to the suggestion that LC degeneration may contribute to the development of AD neuropathology. Heneka MT, Ramanathan M, Jacobs AH, Dumitrescu-Ozimek L, Bilkei-Gorzo A, Debeir T, Sastre M, Galldiks N, Zimmer A, Hoehn M, Heiss WD, Klockgether T, Staufenbiel M. Locus coeruleus degeneration promotes Alzheimer pathogenesis in
Acknowledgements
This work was supported in part by Alzheimer's Disease Core Center grant P30AG-13854 from the National Institute of Aging to Northwestern University. The authors are grateful to Dr. Rademaker for his assistance in biostatistics and the University of Miami Brain Endowment Bank for the tissue specimens.
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