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LETTER TO THE EDITOR
Heterogeneity of the circle of Willis and its implication in hippocampal perfusion
Jose Gutierrez
Department of Neurology, Columbia University, New York, NY, USA
Correspondence to: Jose Gutierrez
710 W 168th St, 6th fl, Suite 639, New York, NY, 10032, USA
E-mail: jg3233@cumc.columbia.edu
We read with interest the paper by Perosa et al. (2020) enti-
tled ‘Hippocampal vascular reserve associated with cognitive
performance and hippocampal volume’. The author reported
that a mixed blood supply of the hippocampus by the
posterior cerebral artery (PCA) and anterior choroidal
artery (AChA) may provide vascular reserve and protect
against cognitive impairment. The work is novel and criti-
cally important, given the relevance of hippocampal injury
in Alzheimer’s dementia and other cognitive disorders. It is
unclear, however, how the authors accounted for the hetero-
geneous configuration of the circle of Willis in their meth-
ods. There is no mention of the role that another anterior
circulation artery, the posterior communicating artery
(Pcomm), may play in hippocampal injury in certain
circumstances.
Animal models exist that support a role of the Pcomm in
causing hippocampal injury. The arterial supply of the
hippocampus has general similarities across different species
of large mammals, especially as it refers to the PCA and
AChA supply. Interestingly, the PCA in cats and sheep is
mostly supplied by the carotid arteries with various degrees
of basilar artery-derived flow contributions (Goetzen and
Sztamska, 1992). In mice, there is an even greater propor-
tion of hippocampal flow derived from the anterior circula-
tion (O
¨zdemir et al.,1999). This predominant anterior
circulation blood supply of the hippocampus in smaller
mammals is likely the result of smaller frontal lobes com-
pared to humans. The large volume of the human frontal
lobes increases the flow demand via the carotids. The pro-
gressive shift of the source of PCA supply towards the verte-
brobasilar system in humans represents an adaptive
hydrodynamic solution to the competing flow demands
(Menshawi et al.,2015). Because of the dominant anterior
circulation blood supply to the hippocampus in smaller
mammals, occlusion of the middle cerebral artery (MCA)
causes hippocampal ischaemia in mice with a hypoplastic
Pcomm or an incomplete circle of Willis (Kitagawa et al.,
1998;O
¨zdemir et al.,1999). Mongolian gerbils are often
used to study ischaemic injury to the forebrain and hippo-
campus because they have a rudimentary basilar-Pcomm
connection and often lack anteroposterior anastomoses
(Yoshimine and Yanagihara, 1983;Laidley et al.,2005).
Consequently, in Mongolian gerbils, occlusion of the
Pcomm or bilateral internal carotid arteries (ICAs) causes
hippocampal ischaemia (Yoshimine and Yanagihara, 1983),
especially in gerbils with an absent or hypoplastic Pcomm
(Laidley et al.,2005;Seal et al.,2006;Ahn et al.,2019).
The shift towards a dominant basilar artery supply of the
hippocampus via PCA in humans is not universal. In fact,
20% of the population lacks one or both PCA P1 segment
(i.e. a foetal PCA, branch of the ICA) (Van Overbeeke et al.,
1991;Gutierrez et al., 2013) and 10% have at least one
hypoplastic P1 segment (Gutierrez et al.,2013;Vrselja et al.,
2014). In other words, a third of the population has an an-
terior circulation dominant blood supply to the distal PCA.
A more detailed description of the blood supply to the
hippocampus and medial temporal lobe regions reveals a
complexity not easily captured by the PCA or the AChA. In
humans, the ambien gyrus is supplied by the anterosuperior
parahippocampal arteries (also known as uncal arteries),
which are branches of the MCA in the anterior aspect,
and branches of the ICA, AChA, and PCA in the posterior
aspect. The ventrolateral region of the entorhinal cortex (an-
terior parahippocampal gyrus) is supplied by the anteroinfe-
rior parahippocampal arteries, which may originate in either
the MCA (specifically as branches from the MCA anterior
temporal artery) or the PCA, and less often from the AChA
(Huther et al.,1998). The anterior hippocampal formation
is supplied by the medial uncal arteries, branches most often
of the AChA and less often of the PCA. Occasionally, medial
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uncal arteries may arise from anastomoses of the anterosu-
perior parahippocampal arteries. The lateral aspect of the
hippocampus and its digitations are supplied by the lateral
uncal arteries, branches of the AChA or the PCA, less often
as branches of the PCA-derived anterior temporal artery or
segmental branches of medial uncal arteries (Huther et al.,
1998). The lateral and medial uncal arteries together supply
the anterior and medial hippocampus and therefore are also
known as anterior and medial hippocampal arteries typically
described as branches of the PCA and less commonly of the
AChA (Marinkovi
cet al.,1992). The areas TF/TH and the
caudal part of the parahippocampal gyrus are supplied by
the posterior parahippocampal arteries, branches of the PCA
(most commonly) or the AChA. The posterior hippocampal
arteries supply the posterior aspects of the hippocampus and
are derived from the PCA in all cases (Huther et al.,1998).
The terminal arterial branches to the hippocampus are also
known as straight or fork arteries (branches of the medial or
posterior temporal arteries). These arteries penetrate the den-
tate gyrus, the subiculum and the body and fimbria of the
hippocampus (Marinkovi
cet al.,1992). The intraparenchy-
mal course of the internal hippocampal arteries is divided in
two; the dorsal arteries and their respective subregional
branches (CA1, CA2, etc.) that pierce the surface of the den-
tate gyrus and the sector arteries that run within the medul-
lary septum (Marinkovi
cet al.,1992;Huang and Okudera,
1997). More often than not there exist anastomoses between
intrahippocampal, parahippocampal, subicular and uncal
arteries (Marinkovi
cet al.,1992;Huang and Okudera,
1997) effectively communicating the ICA and MCA indirect-
ly to the hippocampal arteries and creating a strong network
favouring collateral flow (Goetzen and Sztamska, 1992).
The internal hippocampal arteries do not from anastomoses,
however, and therefore are terminal arteries (Goetzen and
Sztamska, 1992). The average luminal diameter of arteries
supplying the medial temporal lobe including the hippocam-
pusrangesfrom215–335mmwithupto800mmdescribed
in some cases (Marinkovi
cet al.,1992;Huther et al.,1998).
These small arteries are susceptible to siphon-like geometric
deformation in the form of knot-loops and vascular glomer-
uli in the setting of ageing or brain large artery disease
(Goetzen and Sztamska, 1992).
The relative neglect of the circle of Willis configuration
and the Pcomm is a problem with most of the data discussed
in the previous paragraph. Often, the Pcomm is rarely men-
tioned other than as an anatomical referent. Some authors
imply that the PCA (foetal or not) supplies the hippocampus
regardless of whether it originates as a branch of the basilar
artery or of the carotid artery (Goetzen and Sztamska, 1992;
Erdem et al.,1993). We believe that this proposal may be
reasonable. For example, presurgical epileptic patients who
receive an ICA injection (distal to the origin of the AChA) of
amobarbital show amobarbital distribution in the entire
hippocampus if they have a foetal PCA (Urbach et al.,
1999). Unfortunately, this study did not investigate the de-
gree of amobarbital distribution as a function of inverse re-
ciprocal relationship noted by us between the calibre of the
PCA and the Pcomm (Gutierrez et al.,2013). Other data
suggest that patients with strokes due to a carotid dissection,
who have an ipsilateral foetal PCA, present with medial hip-
pocampal ischaemia (Walha et al.,2013). In a large popula-
tion-based study, we found that a larger left Pcomm/PCA
average luminal diameter related to episodic memory and
predicted greater cognitive decline (Gutierrez et al.,2018). In
this context, it would stand to reason to hypothesize that in
individuals with a foetal PCA or a hypoplastic PCA P1 seg-
ment, the ICA provides most of the flow to the P2 and P3
segments of the PCA, from which the hippocampal arteries
originate (Erdem et al.,1993). We surmise then that the ana-
tomical, functional, epidemiological and clinical data pre-
sented above reveal the need to integrate the anatomy of the
circle of Willis in the study of hippocampal blood supply
and the proposed model of hippocampal vascular reserve.
With this in mind, it would prudent for Perosa et al.
(2020) to disclose further details regarding how they inte-
grated the above-described heterogeneity of the circle Willis
in their results, and whether their results would remain the
same by incorporating the contribution of the ipsilateral
Pcomm and/or foetal PCA to the hippocampus blood
supply.
Data availability
Data sharing is not applicable to this article as no new data
were created or analysed in this study.
Funding
Supported by National Institute on Aging (1R01AG057709
and 1R01AG066162).
Competing interests
The author reports no competing interests.
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