Degeneration of the locus ceruleus (LC) and decreased cortical levels of norepinephrine are common findings in Alzheimer's disease (AD), but their significance is unknown. Because the noradrenergic system is accessible to pharmacological intervention, the role of LC degeneration and noradrenergic dysfunction in the pathogenesis and clinical manifestations of AD needs clarification. Hypothetically, loss of noradrenergic innervation could cause microvascular dysfunction and manifest as ischemia. The objectives of this study were to develop a scale for assessment of LC degeneration and to determine whether degeneration of the LC correlates quantitatively with either duration of clinical dementia, overall severity of AD pathology or with measures of ischemic non-focal white matter disease (WMD) in AD. This report is a pathological follow-up of a clinical longitudinal dementia study of 66 consecutive cases of AD without admixture of vascular dementia (VaD) from the Lund Longitudinal Dementia Study, neuropathologically diagnosed between 1990 and 1999. Ten cases of VaD were included for comparative purposes. No correlation between degree of LC degeneration and duration of dementia, AD or WMD severity was found. LC degeneration was significantly more severe in the AD group than in the VaD group. Even though LC degeneration was not associated with WMD or the severity of AD pathology in this AD material, we suggest that clinical studies on the consequences of noradrenergic dysfunction are warranted. Treatment augmenting noradrenergic signaling is available and safe. The marked difference in the level of LC degeneration between AD and VaD cases suggests that LC degeneration could be used as a diagnostic marker of AD.
"Moreover, in AD abnormalities of the dopaminergic system are reported in terms of dopamine neuron degeneration (Allard et al. 1994) and reduced expression of dopamine receptors, mainly involving D1, D3, and D4 receptor subtypes (Kumar and Patel 2007; De Keyser et al. 1990). The neurodegenerative process involves neurons synthesizing amines of the locus coeruleus (Zarow et al. 2003; Lyness et al. 2003; Haglund et al. 2006; Grudzien et al. 2007); in AD patients dopamine concentration is likely reduced due to the degeneration of monoaminergic neurons. The fact that melevodopa failed to promote any effect in control subjects and VA patients, whose dopamine storage mechanisms seem not to be impaired, may indeed suggest a disease-specific reduction of the endogenous dopamine tone in AD patients. "
[Show abstract][Hide abstract] ABSTRACT: Short-latency afferent inhibition (SAI) technique gives the opportunity to non-invasively test an inhibitory circuit in the human cerebral motor cortex that depends mainly on central cholinergic activity. Important SAI abnormalities have been reported in both patients with Alzheimer disease (AD) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a model of "pure" vascular dementia (VD). Interestingly, a normalization of SAI was observed in AD after levo-dopa (L-dopa) administration. We aimed to determine whether the pharmacological manipulation of the dopaminergic system can also interfere with SAI test in CADASIL patients, compared with AD patients and healthy controls. SAI was found to be significantly reduced in both patient groups. L-Dopa significantly increased SAI in the AD patients, while it failed to restore SAI abnormality in CADASIL patients. Therefore, L-dopa-mediated changes on SAI in AD patients seem to be a specific effect. The present study supports the notion that relationship between acetylcholine and dopamine systems may be specifically abnormal in AD. L-Dopa challenge may thus be able to differentiate the patients with AD or a mixed form of dementia from those with "pure" VD.
[Show abstract][Hide abstract] ABSTRACT: Damage to the locus ceruleus, with a subsequent decrease of CNS noradrenaline, occurs in a wide range of neurodegenerative, demyelinating and psychiatric disorders. The cause of the initial locus ceruleus damage remains unknown. Recently, inorganic mercury was found to enter human locus ceruleus neurons selectively. This has led to the formulation of a new hypothesis as to the cause of these disorders.
Toxicants enter locus ceruleus neurons selectively, aided by the extensive exposure these neurons have to CNS capillaries, as well as by stressors that upregulate locus ceruleus activity. The resulting noradrenaline dysfunction affects a wide range of CNS cells and can trigger a number of neurodegenerative (Alzheimer's, Parkinson's and motor neuron disease), demyelinating (multiple sclerosis), and psychiatric (major depression and bipolar disorder) conditions.
This hypothesis proposes that environmental toxicants entering the locus ceruleus can give rise to a variety of CNS disorders. Proposals are made for experiments to gain further evidence for this hypothesis. If it is shown that toxicants in the locus ceruleus are responsible for these conditions, attempts can be made to prevent the toxicant exposures or to remove the toxicants from the nervous system.
Medical Hypotheses 11/2013; 82(1). DOI:10.1016/j.mehy.2013.11.016 · 1.07 Impact Factor
"Extensive LC degeneration is nearly universal in AD [9-13] and is among the earliest pathologies [11,14,15], with LC neuropathology detectable as early as 10 years before neurocognitive signs [16-18]. Alterations in NE have long been known to be linked to cognitive, mood and neuropsychiatric symptoms [6,19-24]. "
[Show abstract][Hide abstract] ABSTRACT: The Alzheimer's disease (AD) epidemic is a looming crisis, with an urgent need for new therapies to delay or prevent symptom onset and progression. There is growing awareness that clinical trials must target stage-appropriate pathophysiological mechanisms to effectively develop disease-modifying treatments. Advances in AD biomarker research have demonstrated changes in amyloid-beta (Aβ), brain metabolism and other pathophysiologies prior to the onset of memory loss, with some markers possibly changing one or two decades earlier. These findings suggest that amyloid-based therapies would optimally be targeted at the earliest clinically detectable stage (such as mild cognitive impairment (MCI)) or before. Postmortem data indicate that tau lesions in the locus coeruleus (LC), the primary source of subcortical norepinephrine (NE), may be the first identifiable pathology of AD, and recent data from basic research in animal models of AD indicate that loss of NE incites a neurotoxic proinflammatory condition, reduces Aβ clearance and negatively impacts cognition - recapitulating key aspects of AD. In addition, evidence linking NE deficiency to neuroinflammation in AD also exists. By promoting proinflammatory responses, suppressing anti-inflammatory responses and impairing Aβ degradation and clearance, LC degeneration and NE loss can be considered a triple threat to AD pathogenesis. Remarkably, restoration of NE reverses these effects and slows neurodegeneration in animal models, raising the possibility that treatments which increase NE transmission may have the potential to delay or reverse AD-related pathology. This review describes the evidence supporting a key role for noradrenergic-based therapies to slow or prevent progressive neurodegeneration in AD. Specifically, since MCI coincides with the onset of clinical symptoms and brain atrophy, and LC pathology is already present at this early stage of AD pathogenesis, MCI may offer a critical window of time to initiate novel noradrenergic-based therapies aimed at the secondary wave of events that lead to progressive neurodegeneration. Because of the widespread clinical use of drugs with a NE-based mechanism of action, there are immediate opportunities to repurpose existing medications. For example, NE transport inhibitors and NE-precursor therapies that are used for treatment of neurologic and psychiatric disorders have shown promise in animal models of AD, and are now prime candidates for early-phase clinical trials in humans.
Alzheimer's Research and Therapy 04/2013; 5(2):21. DOI:10.1186/alzrt175 · 3.98 Impact Factor
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