The intrinsic cholinergic innervation of the cortical microvessels contains both subcortical pathways andlocal cortical interneurons mediated by muscarinic and nicotinic acetylcholine receptors. Stimulation ofthis system leads to vasodilatation. In the extrinsic innervation, choline acts as a selective agonist forthe �7-nicoticinic acetylcholine receptor on the sympathetic nerves to cause vasodilatation, and throughthis mechanism, cholinergic modulation may affect this sympathetic vasodilatation. Alzheimer’s diseaseis characterized by a cerebral cholinergic deficit and cerebral blood flow is diminished. Cholinesteraseinhibitors, important drugs in the treatment of Alzheimer’s disease, could influence the cerebral bloodflow through stimulation of the intrinsic cholinergic cerebrovascular innervation. Indeed, cholinesteraseinhibitors improve cerebral blood flow in Alzheimer patients who respond to treatment. Further, cere-brovascular reactivity and neurovascular coupling are impaired in Alzheimer’s disease and both can beimproved by cholinesterase inhibitors. Conversely, cholinesterase inhibitors inhibit the �7-nicoticinicacetylcholine receptor on extrinsic sympathetic nerves and thus may impair vasodilatation. The net out-come of these opposing effects in clinical practice remains unknown. Moreover, it is uncertain whether
the regulation of cerebral blood flow during blood pressure changes (cerebral autoregulation) is impairedin patients with Alzheimer’s disease. Technological developments now allow us to dynamically measureblood pressure, cerebral blood flow, and cerebral cortical oxygenation. Using simple maneuvers like sin-gle sit–stand and repeated sit–stand maneuvers, the regulation of cerebral perfusion in patients withAlzheimer’s disease can easily be measured. Sit–stand maneuvers can be considered as a provocationtest for cerebral autoregulation, and provide excellent opportunities to study the cerebrovascular effects of cholinesterase inhibitors.
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∗ Corresponding author at: Radboud University Nijmegen Medical Centre, 925 –epartment of Geriatric Medicine, P.O. Box 9101, 6500 HB Nijmegen, The Nether-
Three major research findings have pointed towards a possibly
erebrovascular role of the cholinergic neural system in Alzheimer’s
impaired cholinergic regulation of cerebral blood flow (CBF) inpatients with Alzheimer’s disease (AD). In the mid-1970s, thediscovery of both the emerging role of acetylcholine in memoryand learning, and the loss of cholinergic innervation in the brain of
atients with Alzheimer’s disease (AD) gave rise to the cholinergicypothesis of AD [1]. Afterward, starting in the late 80 s, severaltudies have investigated the role of the cholinergic system in thennervation and control of the cerebral blood vessels since theseessels appeared to be surrounded by nerve fibers originatingrom both peripheral nerve ganglia and intrinsic brain neurons [2].hese perivascular nerves were found to have an important role inhe regulation of the tone of the cerebral vasculature, and therebyrain perfusion. In AD, the cortical microvessels show denervation,nd in particular perivascular cholinergic nerve terminals areargely lost [3]. The cortical CBF in AD patients is severely impaired4,5] and in fact, this reduction in CBF is considered to be anarly manifestation of this disease. The combination of thesehree observations has led to the cholinergic-vascular hypothesis:he loss of cholinergic vascular innervation is responsible for orontributes importantly to the impairment in CBF. Along theseines, cholinesterase inhibitors (ChEIs), the commonly used drugsn the treatment of AD, could have a significant effect on theerebral circulation [6] and may even exert their effects mainly by
Please cite this article in press as: Van Beek AHEA, Claassen JAHR. The cdisease. Behav Brain Res (2010), doi:10.1016/j.bbr.2009.12.047
mproving cerebrovascular function [7].This review will focus on the cholinergic innervation of the cere-
rovascular bed, on the impairment in the regulation of cerebrallood flow (CBF) in AD, and finally on the influence of ChEIs on this
mpaired regulation of CBF.
ig. 1. Schematic overview of the cholinergic innervation of the cerebrovasculature.epresent a cholinergic innervations of the vessels in all situation. The dashed lineion. The dotted line indicates that the presence of the nAch receptor has not direhen the basal forebrain is stimulated.
PRESSral Brain Research xxx (2010) xxx–xxx
2. Cholinergic innervation of cerebral blood vessels
The vascular tree of the brain originates from cerebral largearteries at the base of the brain at the circle of Willis. These largearteries travel through the dura mater and then branch into smallerpial arteries that travel on the surface of the brain in the sub-arachnoid space [5]. Next, these pial arteries on the surface branchinto penetrating intracerebral arteries, arterioles, and the capillarymicrovasculature [4]. In general, most blood vessels in the brainare innervated by nerve fibers that contain acetylcholine and othervasoactive substances [8]. At the brain’s surface, these fibers orig-inate from the peripheral ganglia which are part of the autonomicnerve system whereas further downstream, these perivascularfibers originate from intrinsic brain neurons. This subdivision isdescribed as the extrinsic and intrinsic innervations of cerebral ves-sels, respectively. Below, we will review the cholinergic branch ofthese innervations. We have provided a schematic overview of thischolinergic innervation in Fig. 1.
erebrovascular role of the cholinergic neural system in Alzheimer’s
2.1. Intrinsic innervation
The intrinsic cholinergic innervation of the cortical microvesselscontains both subcortical pathways and local cortical interneu-rons mediated by muscarinic and nicotinic acetylcholine receptors.
Flow chart of the cholinergic innervations of the cerebral vessels. Solid linesrepresents a role for the cholinergic innervations only in pathological situa-
ctly been confirmed; blockade of the nicotinic receptor inhibits vasodilatation
he basal forebrain is the major source of brain cholinergic neu-ons and comprises the medial septum, diagonal band of Broca,nd the nucleus basalis of Meynert. The medial septum andiagonal band provide cholinergic projections to the hippocam-us, and the nucleus basalis projects to the cortex. The nucleusasalis also has projections to perivascular cholinergic nerve ter-inals in the frontoparietal cortex [3,9], and upon stimulation
hese projections induce a significant dilation of vessels medi-ted by muscarinic receptors [10]. Possibly, nicotinic acetylcholineeceptors also play a role as nicotinic antagonists block vasodi-atation, although these receptors have thus far not directly beendentified in intraparenchymal vessels to our knowledge. Duringhis cholinergic cortical vasodilatation induced by stimulation ofhe basal forebrain, nitric oxide production is an essential fac-or. This is thought to reflect both the activation of nitrergicnterneurons and a direct effect of perivascular acetylcholineelease.
Further, this subcortical pathway also exerts its effect throughABA (�-aminobutyric acid) interneurons. These interneuronsppear strategically positioned to translate incoming neuronal sig-als from various subcortical afferents into adapted local neuronalnd vascular responses, including those originating from basal fore-rain cholinergic neurons [11].
.2. Extrinsic innervation
The extrinsic innervation of the brain vessels comprises bothhe both sympathetic and parasympathetic nerves of the autonomicystem. Both divisions of the autonomic nervous system use acetyl-holine as a preganglionic neurotransmitter. The parasympatheticostganglionic neurotransmission is also cholinergic, whereas theympathetic postganglionic system essentially is non-cholinergic.he parasympathetic system is a potent dilator of brain vesselspon stimulation, however, it does not seem to play a signifi-ant role in physiological cerebrovascular responses. In the nerveell bodies of the parasympathetic otic and sphenopalatine gan-lia, the classic neurotransmitter is acetylcholine [12]. Togetherith the trigeminovascular pathway, the latter innervation plays
n important role in ischemia and migraine headache [2]. The sym-athetic innervation to the cerebral vasculature is largely via theuperior cervical ganglion. A possible role for this system lies inhe pressure autoregulation mechanism of the brain blood ves-els. For example, during a decline in cardiac output an increasedympathetic drive may also contribute to cerebral vasoconstriction13]. However, controversy remains as to whether the autonomicerve system truly has a role in cerebral autoregulation—i.e. inhe active control of vasomotor tone to counteract blood pressurehanges [40]. Although the sympathetic system is non-cholinergic,here is a potentially relevant cholinergic interaction in this sys-em. A subtype of the nicotinic acetylcholine receptor (7-nAChR,
receptor with neuroprotective effects and effects on memory)s located on the perivascular postganglionic sympathetic nerves.his receptor mediates vasodilatation as follows: upon activationby nicotine or choline), the postsynaptic sympathetic perivasculareurons release norepinephrine, which then acts on presynapticdrenoceptors on neighboring nitrergic perivascular interneurons,ith release of NO and subsequent vasodilatation. Importantly, in
nimal studies it was shown that cholinesterase inhibitors blockhe 7-nAChR and, therefore, inhibit vasodilatation [14].
.3. Neurovascular coupling
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An important characteristic of cerebral blood vessels is theirlose interaction with neurons and glia (astrocytes, microglia,ligodendrocytes). Neurons, glia, and vascular cells (endothelium,mooth muscle cell or pericytes, adventitial cells) are closely
PRESSral Brain Research xxx (2010) xxx–xxx 3
related, not only structurally, but also functionally. To highlightthe functional relation, the term ‘neurovascular unit’ was intro-duced, referring to an integrated system that modulates local CBF inresponse to brain activity or injuries [15]. The mechanisms modu-lating this neurovascular coupling are mediated by different agents,i.e. extracellular ions, metabolic products, and vasoactive neuro-transmitters. The latter are released during neural activity, andacetylcholine is one of these neurotransmitters.
3. Alzheimer’s disease
The leading hypothesis of AD is the amyloid hypothesis, whichstates that an imbalance between the production and clearanceof the amyloid beta (A�) protein in the brain is the initiatingevent of the disease, ultimately leading to neuronal degenera-tion and dementia [16]. The last decade however, research hasalso focused on the cerebrovascular factors in AD and mountingevidence indicates that cerebrovascular factors play an importantrole in the pathogenesis of AD [17]. Epidemiological studies high-light the important contribution of vascular risk factors in AD [18]and evidence from studies of neuropathology indicates that cere-brovascular disease plays an additive or synergistic role in AD [19].Structure and function of cerebral vessels are affected and impairedat the level of the large vessels, the pial and intracerebral arteries,and at the level of the capillaries [5].
3.1. Cholinesterase inhibitors in the treatment of Alzheimer’sdisease
The cholinergic hypothesis of AD, developed in the 70 s, sug-gests that a dysfunction of acetylcholine containing neurons inthe brain contributes substantially to the cognitive decline in AD[20]. Cholinesterase inhibitors (ChEIs), a drug therapy based on thishypothesis, are used to treat AD. They reduce the synaptic break-down of acetylcholine and thus partially correct the cholinergicdeficit. These ChEIs however, show very global and only mod-est improvements in cognition, attention, and executive functions,and are characterized by a heterogeneous and variable treatmentresponse, which furthermore is not specific for AD patients [21–24].The cholinergic hypothesis fails to account for these drawbacksand the clinical effect of ChEIs may be better explained by thecholinergic-vascular hypothesis [7]. According to this hypothesis,ChEIs act primarily, or at least for a substantial part, by augmentingcerebral perfusion [7].
3.2. Cerebrovascular effects of cholinesterase inhibitors
ChEIs raise the concentration of acetylcholine in the brain andthus could induce vasodilatation with a subsequent increase incerebral blood flow through stimulation of the intrinsic inner-vation of the cerebral vessels. In pharmacological experiments,it has been demonstrated that anti-cholinergic drugs reduce CBFand cholinergic drugs increase CBF in young and aged humans[25,26]. In AD patients, the longer term outcome of treatment withChEIs on regional cerebral blood flow measured with computedtomography using radio nuclides has been extensively investigated[27–33]. AD patients who responded to treatment showed eitherimprovement or stabilization of CBF [34], whereas non-respondershad a progressive decline in CBF [35]. This increase in CBF in ADpatients after treatment with ChEIs is most likely a direct vascu-
erebrovascular role of the cholinergic neural system in Alzheimer’s
lar effect and not a consequence of an increase in regional cerebralmetabolism. Blocking cortical neuronal activity did not prevent theincrease in CBF induced by a cholinergic agonist [36] and electri-cal stimulation of the nucleus basalis of the rat augmented CBFwithout an increase in metabolic activity [37,38]. Further, in AD
atients treated with ChEIs, the effects on CBF, paralleled by clini-al effects, preceded the effects on glucose metabolism by months39].
The role of the autonomic nerve system in control of the cere-ral circulation, i.e. the extrinsic system, awaits further elucidation40]. As indicated above, there is a potential interaction at the sitef the 7-nAChR of postganglionic sympathetic perivascular nerves.holinesterase inhibitors block the action of this receptor and thusay impair vasodilatation [14].
.3. Influence of cholinesterase inhibitors on the regulation oferebral blood flow
The brain is extremely dependent on a continuous blood sup-ly and has several defense mechanisms to ensure maintenance oferebral perfusion. The first line of defense is the control of the car-iovascular system to maintain a stable blood pressure. The second
ine of defense, termed cerebral autoregulation, counteracts theerebrovascular effects of the normal fluctuations in blood pres-ure that occur both spontaneously and during normal activities. Ahird mechanism regulates the distribution of cerebral blood flowccording to the functional activity of the different brain regions,alled neurovascular coupling [4]. In addition, CBF can be increasedr decreased by a change in arterial CO2. Hypercapnia (increasedO2) may cause a 3–5% increase in CBF per mmHg rise in end-tidalO2, whereas hypocapnia (decreased CO2) can reduce CBF by 2–3%er mmHg reduction in end-tidal CO2 [41].
The technological development of transcranial Doppler ultra-onography (TCD) by Aaslid has made it possible to measureBF-velocity non-invasively and with a very high temporal reso-
ution (<0.1 s) in one of the supplying arteries of the brain, mostlyhe middle cerebral artery [42]. The changes in CBF-velocity in
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his artery represent changes in CBF on the condition that theiameter of this large cerebral vessel does not change [43]. UsingCD, it has been demonstrated that in patients with AD the CO2-nduced vasodilatation (cerebrovascular reactivity) is impairednd that the coupling between local CBF and neuronal activ-
able 1egulation of cerebral perfusion in Alzheimer’s disease, and the influence of cholinestera
Authors Study sample CBF measurementtechnique
Bar et al. [46] Alzheimer’s disease = 17Vascular dementia = 17Control young = 20Control old = 20
ity is disturbed [44,45]. Three studies investigated the effect ofChEIs on cerebrovascular reactivity and neurovascular couplingin patients with AD [45–47]. From these studies, it can be con-cluded that cerebrovascular reactivity and neurovascular couplingare impaired in AD patients, and that both can be improved byChEIs [45–47]. These data thus support the cholinergic-vascularhypothesis. In Table 1, we provide a detailed overview of thesestudies. Of note, in addition to the TCD measurements, Bar etal. [46] added measurements with near-infrared spectroscopy(NIRS) and Rosengarten et al. [47] added electro encephalography(EEG) measurements. NIRS provides information on the cere-bral cortical oxygenation by measuring concentration changes ofoxygenated and deoxygenated haemoglobin, whereas EEG mea-sures the evoked potential from electrical recordings of the fieldpotential.
3.4. Options for further research
The term dynamic cerebral autoregulation refers to the abilityof the brain to maintain a stable CBF despite fast changes in bloodpressure. Together with dynamic blood pressure measurementsenabled by Finapres (servo-controlled finger photoplethysmogra-phy), TCD offers good prospects to measure cerebral autoregulationnon-invasively and dynamically [43]. Using TCD and Finapres, wehave recently shown that AD patients have a higher cerebrovascularresistance, which was unexplained by brain atrophy [48]. Addi-tionally, the cerebral hemodynamics were altered in AD patientscompared to healthy controls, whereas cerebral autoregulationappeared unaffected [48]. However, the patients in this study werealready treated with ChEIs, and it is very likely that this will haveinfluenced results. Therefore, whether or not cerebral autoregula-tion is impaired in untreated AD patients and whether ChEIs affect
erebrovascular role of the cholinergic neural system in Alzheimer’s
this regulation remains unknown. Further, TCD does not provideinformation on cerebral tissue oxygenation and offers no informa-tion on the regulation of the microcirculation during blood pressurechanges in AD patients. NIRS measurements, which provide infor-mation on the changes of the oxygenation of the cerebral cortex,
se inhibitors.
CBF—regulationmechanism
Cholinesteraseinhibitor
Conclusion
CerebrovascularReactivity—CO2
inhalation
Galantamine5 weeks
In Alzheimer patients,vascular reactivity asmeasured by TCD wasseverely impaired, butnot cerebraloxygenation (NIRS)during hypercapnia.Galantamine improvedvascular reactivity.
A.H.E.A. Van Beek, J.A.H.R. Claassen / Behavioural Brain Research xxx (2010) xxx–xxx 5
Fig. 2. Example of the blood pressure and cerebral perfusion response during asingle sit–stand maneuver. Continuous beat-to-beat blood pressure (upper panel),cerebral blood flow (middle panel), and frontal cortical oxygenation measure-ments (lower panel) using Finapres, transcranial Doppler ultrasonography, andnear-infrared spectroscopy, respectively, during a sit to stand maneuver in a healthyosa
tbcmT
oCAuCtppliqstt[
Fig. 3. Example of the blood pressure and cerebral perfusion response during arepeated sit–stand maneuver. Representative beat-to-beat data from one healthycontrol during a repeated sit stand maneuver. The subject performed repeated
the influence of cholinesterase inhibitors on this regulation. The
ld subject. The line represents the mean of three single sit–stand maneuvers. Theubject starts standing after 60 s. Beat-to-beat data were resampled at 2 Hz to createn equal time base.
ogether with Finapres and TCD, would provide information onoth dynamic cerebral autoregulation and on the regulation oferebral cortical oxygenation. Since in AD especially the cerebralicrovessels are affected [5], the addition of NIRS to Finapres and
CD seems very valuable.To assess dynamic cerebral autoregulation and the regulation
f the cortical microcirculation, the observation of the response ofBF and cortical oxygenation to an alteration in BP are essential.simple single sit–stand maneuver offers a method which can be
sed in (frail) older patients to induce changes in blood pressure,BF, and cortical oxygenation, which in turn can be used to quantifyhe regulation of cerebral perfusion and oxygenation during bloodressure changes [49]. Fig. 2 provides the response of the threearameters upon standing in a healthy old volunteer. Also, base-
ine measurements and the assessment of spontaneous oscillationsn blood pressure, CBF, and cortical oxygenation offer a method touantify the regulation of cerebral perfusion. This method however,
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uffers from the weakness of the spontaneous oscillations in thehree parameters. Then, repeated sit–stand maneuvers can be usedo augment the oscillations in BP, CBF, and cortical oxygenation50]. In Fig. 3, we provide an example of the BP, CBF, and corti-
sit–stand at 0.05 Hz, i.e. 10 s sit followed by 10 s stand, during 100 s. The upper panelpresents the blood pressure response, the middle panel cerebral blood flow, and thelower panel changes in frontal cortical oxygenated haemoglobin. The data wereinterpolated at 2 Hz.
cal oxygenation response to a repeated sit–stand maneuver in ahealthy older volunteer.
4. Conclusion
The cerebral vessels are cholinergically modulated by boththe extrinsic and intrinsic nerve system. Alzheimer patients suf-fer from a brain cholinergic deficit and cerebral blood flow isdiminished. Further, the cerebrovascular reactivity and neurovas-cular coupling is impaired in these patients. In Alzheimer patientswho respond to cholinesterase inhibitors, the cerebral blood flowincreases due to a direct vascular effect. Cholinesterase inhibitorsimprove cerebrovascular reactivity and neurovascular coupling.Whether or not dynamic cerebral autoregulation is impaired indrug-naïve patients remains unknown, and the same is true for
erebrovascular role of the cholinergic neural system in Alzheimer’s
use of sit–stand maneuvers with measurements of Finapres, tran-scranial Doppler ultrasonography, and near-infrared spectroscopyoffers good prospects to further investigate the dynamic regula-tion of cerebral blood flow and cerebral cortical oxygenation in
lzheimer patients before and after treatment with cholinesterasenhibitors.
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