The basal forebrain cholinergic system (BFCS) is the major source of acetylcholine in the brain and provides its primary cholinergic input to the hippocampus and
entorhinal cortex, but it also projects to all cortical areas and to the amygdala (for a review see (Auld et al., 2002). Figure 6 illustrates the cholinergic pathways that originate from the Ch4 region of the nucleus basalis of Meynert in the human brain.
The medial bundle supplies areas close to the midline including olfactory, cingulate, retrosplenial and medial occipital cortex. The lateral pathway supplies the rest of the cortex via two branches. The two pathways merge anterior in the orbitofrontal area and posterior in the occipital area. Figure 7 illustrates the major cholinergic afferents from the BFCS to the neocortex, entorhinal cortex, amygdala and hippocampus.
Figure 6. Cholinergic pathways in the brain.
This figure illustrates the medial (green) and lateral cholinergic pathways that originate from the Ch4 region of the nucleus basalis of Meynert in the human brain.
The medial bundle supplies areas close to the midline including olfactory, cingulate, restrosplenial and medial occipital cortex. The lateral pathway supplies the rest of the cortex via two branches (red and orange). The two pathways merge anterior in the orbitofrontal area and posterior in the occipital area. Sections proceed from rostral (A) to ventral (C). (Selden et al., 1998). Reproduced by permission of Oxford University Press.
Function
The function of Ach and therefore cholinergic neurotransmission in memory and attention processing is discussed in detail in §1.7.1.
The BFCS in AD and AMCI
From the comprehensive cholinergic innervation of the cerebrum discussed above, it follows that AD neuropathology affecting the basal forebrain nuclei could diminish cholinergic neurotransmission to all these areas in AMCI and AD. Research findings support this notion as cholinergic neurotransmission is prominently affected in AD where degeneration of cholinergic neurones of the basal forebrain nuclei leads to diminished cortical and hippocampal input (Francis et al., 1999; Perry et al., 1999;
Sarter et al., 2003). The status of cholinergic neurotransmission in AMCI is less clear.
Post mortem reports suggest reduced numbers of basal forebrain cholinergic neurones (Mufson et al., 2002), but upregulated cholinergic neurotransmission as indicated by elevated levels of cholinesterase acetyltransferase (responsible for acetylcholine synthesis) (DeKosky et al., 2002). Recent animal studies suggest that upregulated cholinergic neurotransmission may be caused by noradrenergic deficits whilst AMCI is associated with AD neuropathology in the locus coeruleus that is the source of
cerebral noradrenaline. We look at this in detail in the following section (§1.6.5).
Findings from functional neuroimaging studies are more consistent. PET studies of in vivo activity of acetylcholinesterase (AChE), the enzyme that rapidly metabolises acetylcholine, have found a similar pattern of deficiency in AMCI as seen in AD (Rinne et al., 2003). Furthermore, decreased cortical AChE activity in AMCI
predicted conversion to AD (Herholz et al., 2005). A recent PET study using a ligand that binds to the most prevalent cortical acetylcholine receptor (nicotinic α4β2
subtype) reported significantly decreased hippocampal, caudate, frontal cortex, temporal cortex, parietal cortex, anterior and posterior cingulated binding in AMCI and AD patients compared to controls (Sabri et al., 2008). Acetylcholine receptor binding in MTL positively correlated with MMSE scores, indicating that better global cognition associates with the availability of more cholinergic receptors. Interestingly, it appears that nicotinic acetylcholine receptor binding correlates more with attention than with episodic memory as significant correlations have been demonstrated
between receptor binding (whole brain, frontal association cortex, parietal cortex) and measures of attention, with no correlations evident between receptor binding and episodic memory in any cortical area in mild AD (Kadir et al., 2006). In summary, these findings indicate that AMCI and AD are associated with reduced cholinergic innervation and reduced neuronal cholinergic receptors on the background of very early pathology in the BFCS, the source of Ach.
Animal models indicate that BFCS lesions can cause memory deficits in the absence of hippocampal damage, apparently mediated via impaired attentional modulation rather than specific memory impairment (Auld et al., 2002; Chiba et al., 1999). The cholinergic hypothesis of cognitive impairment in AD may therefore explain impairments in memory and non-memory functions such as attention
(Lawrence and Sahakian, 1995; Parasuraman et al., 1995; Parasuraman et al., 1992), which are regulated by the BFCS (for a review see (Sarter et al., 2005)).
Several lines of evidence indicate regulation of attentional processing via cholinergic input to sensory cortices where it improves the signal-to-noise ratio (signal-driven or bottom-up modulation), and to frontal and parietal cortex where it regulates processing in selective cortical areas (task driven or top-down modulation) (Sarter et al., 2005). BFCS pathology appears to be the earliest lesions in AD and it could affect the MTL via reduced cortical cholinergic innervation disrupting cognitive modulation, explaining the amnesia and impairment on other cognitive functions.
Figure 7 illustrates the cholinergic innervation of various brain areas. The entorhinal cortex and hippocampus receive inputs from the medial septal nucleus and diagonal band of Broca whilst the nucleus basalis of Meynert projects to the amygdala and neocortical association areas. This illustrates how neuropathology affecting any of the nuclei that comprise the BFCS can affect memory and attention either directly or indirectly.
Figure 7. Cerebral cholinergic afferents.
The figure illustrates the major cholinergic afferents (dashed light blue lines) from the BFCS to the neocortex, entorhinal cortex, amygdala and hippocampus.
1.6.5 The Role of the Brainstem Locus Coeruleus in Attention and Memory The locus coeruleus contributes substantially to the control of attention and memory.
Its role in cognitive control, small size and vulnerability to AD neuropathology highlight it as one of the areas that may be key in the development of AD, similar to the BCFS discussed above (§1.6.4).
Anatomy and function
The locus coeruleus is located in the tegmentum in the brainstem and the sole source of noradrenaline to the neocortex, cerebellum, hippocampus and most of the thalamus.
Noradrenaline from the locus coeruleus regulates attentional selection, arousal, and stress reactions related to environmental challenges (Aston-Jones, 2005; Foote et al., 1983).
Animal studies indicate that unpredictable but relevant stimuli activate the locus coeruleus more than irrelevant stimuli and this holds for multiple sensory modalities.
The locus coeruleus also shows increased activation under other stressful situations including loud noise, punishment, pain, emotionally aversive images of snakes and angry faces (Raizada and Poldrack, 2008).
Lesions of the locus coeruleus, therefore noradrenergic lesions, affect learning in animal models and exacerbate the amnestic effects of cholinergic deficits induced by either muscarinic receptor blockade or BFCS lesions, on new learning and recall of pre-lesion episodic memory (Abe et al., 1997; Murchison et al., 2004; Ohno et al., 1993; Ohno et al., 1997). Furthermore, experimentally induced lesions of the locus coeruleus promote amyloid plaque deposition and neuronal loss in projection areas whilst sparing non-projection areas (Heneka et al., 2002; Heneka et al., 2006). These
lesions also reduce cerebral glucose metabolism and aggravates memory deficits in a transgenic animal model of AD. These findings indicate that noradrenergic lesions result in cognitive and metabolic changes characteristic of AD.
Activation in the locus coeruleus, and in the right PFC, appears to correlate with sudden unpredictable increases in task difficulty that constitutes a challenge to attentional resources. This was demonstrated by an fMRI study of attentional resource allocation during challenging attentional conditions (Raizada and Poldrack, 2008).
The task for this study employed high intensity visual (flashed white disc) and auditory stimuli (bursts of noise) with unpredictable onset. A period of stimulation would start with either visual or auditory, or visual and auditory stimulation with the latter condition being the most challenging. Increased activation in the locus coeruleus and right PFC occurred during the most challenging attentional condition. These findings revealed a close correlation between activation in these two areas, indicating a high level of functional connectivity that is supported by structural and functional connectivity studies in animals. Furthermore, they demonstrated close correlation between activation in these areas and task difficulty; however, PFC activation increased gradually whilst the brainstem only activated during the most challenging conditions. Activation in the locus coeruleus was also correlated with activation in the visual, auditory and parietal cortices. The locus coeruleus is the main source of
noradrenaline to the cortex and this pattern of correlation mirrors that of the known widespread projections from the locus coeruleus. The authors suggested their findings indicate that meeting attentional demands on challenging tasks are mediated by a frontal-brainstem network wherein the brainstem signals the onset of a challenging attentional condition and the right PFC allocates cognitive resources.
The locus coeruleus in AD and AMCI
AD neuropathology in the locus coeruleus has long been implicated in the pathogenesis of AD and several studies have revealed prominent neuronal loss (reaching 70% in the rostral nucleus) and significant reduction of cortical and limbic NA levels in AD (Grudzien et al., 2007; Heneka, 2009). The reduction of
noradrenaline concentration is highly correlated with disease progression, memory deficits and cognitive impairment. Findings indicate that more extensive neuronal loss in the locus coeruleus correlates better with disease progression compared to
cholinergic cell loss in the in the nucleus basalis of Meynert (Forstl et al., 1994;
Zarowet al., 2003). Meta-analysis of locus coeruleus neuronal loss (311 brains from 24 autopsy studies) indicates that AD patients invariably had substantially reduced cell counts (effect sizes = 2.28; 95% confidence interval = 2.06–2.51) (Lyness et al.2003). Altered activation in the locus coeruleus in AMCI may be caused by NFTs that occur therein in AMCI and AD; the number of NFTs correlate inversely with cognitive performance as measured by the MMSE (Grudzien et al., 2007).
The locus coeruleus contain a small number of neurones, approximately 20 000 in total, therefore minor pathological lesions can have widespread effects on cognition. Serotonin release in the hippocampus, and Ach release in the hippocampus and nucleus basalis of Meynert is regulated (inhibited) by locus coeruleus derived NA (Siniscalchi et al., 1994), and serotonin and Ach are upregulated in MCI compared to both age-matched controls and AD patients (DeKosky et al., 2002; Truchot et al., 2008). Animal studies reveal that chemical ablation of the locus coeruleus can
upregulate Ach and serotonin metabolism similar to that reported in MCI (Jackisch et al., 2008). These findings suggest that AD neuropathology in the locus coeruleus impairs noradrenergic outflow to the cortex and hippocampus in AMCI, resulting in
unopposed serotonin and Ach release. Furthermore, findings that indicate synaptically linked noradrenergic input from the locus coeruleus to the nucleus basalis of Meynert suggest direct modulation of Ach release from the latter by the former (Jones and Yang, 1985; Smiley et al., 1999). This has lead to the suggestion that degeneration of the locus coeruleus would have to precede degeneration of the nucleus basalis of Meynert (and raphe nucleus) in order to give rise to the observed upregulation of Ach metabolism in AMCI, followed by the reduction that marks advanced AD (Heneka, 2009).
The locus coeruleus in ageing
Locus coeruleus noradrenaline signalling may also play a role in ageing. Performance on certain attentional tasks can be restored in aged rats to levels seen in young
animals by electrical stimulation of the locus coeruleus. Furthermore, memory is enhanced by pharmacological manipulation to increase locus coeruleus activity, intraventricular transplantation of locus coeruleus neurones, and by direct
intraventricular infusion of noradrenaline ((Heneka, 2009) and references therein).
The beneficial effects of increased noradrenergic neurotransmission by these
manipulations suggest that early AD neuropathology in the locus coeruleus in AMCI can exacerbate the cognitive deficits caused by BFCS pathology. However, it remains to be established if similar locus coeruleus stimulation will be beneficial in AMCI and AD where neuropathology affects connectivity.
Taken together, these findings indicate that AD neuropathology is likely to be present in the locus coeruleus in AMCI and that it can have widespread cortical effects that can contribute to attention and memory deficits.
Summary
This section has highlighted the interactions between memory, attention, the central executive, PFC, BFCS and locus coeruleus. Attention is regulated in sensory cortices by the central executive via the PFC and BFCS, and both these areas are regulated by the locus coeruleus. Memory is regulated in the MTL by the central executive via the PFC, BFCS and locus coeruleus. In addition, memory and attention closely interact. It is also apparent how neuropathology affecting the BFCS and locus coeruleus very early in the course of AD may account for the widespread cognitive deficits
associated with AD. In the following section would take a closer look at acetylcholine and acetylcholinesterase inhibitor treatment.
1.7 Acetylcholine and Acetylcholinesterase Inhibitor Treatment Acetylcholine (Ach) is a neurotransmitter in both the central and peripheral nervous systems where it functions as a neuromodulator. The cortical effects of the
cholinergic system, comprised of the cholinergic neurons and Ach, are predominantly excitatory. Cholinergic function plays a role in arousal and reward mechanisms and in the regulation of sensory attention and sustained attention. AD neuropathology affects cholinergic neurotransmission by damaging cholinergic neurons in the BFCS and cholinergic axons. In this section, we look at the role of acetylcholine in memory and attention before we look at acetylcholine esterase and acetylcholinesterase inhibitors.
I will discuss the treatment effects of acetylcholinesterase inhibitors on attention in health and on cognitive and behavioural impairments in AD and AMCI
1.7.1 The Role of Acetylcholine in Memory and Attention