C. H. Yang et al.

AC

B
DFigs. 2A–DFig. 2A–D. Immunohistochemistry of cerebral amyloid angiopathies (CAAs).
A: Immunostaining for amyloid β42 (Aβ42). In larger meningeal arteries, small positive areas are limited to themedia adjacent to the adventitia but smaller cortical arteries are intensely stained in their whole walls (arrows).
The occipital cortex in Alzheimer’s disease (AD) (Patient 2).
B: An adjacent section immunostained with Aβ40. Positive areas are larger than Aβ42 but smaller cortical arteries
are negative (arrows). A, B: original magnification, × 40.
C: Immunostaining for Aβ40 of an artery in the occipital cortex, showing complete replacement of the wall by Aβ40.
The occipital cortex from AD (Patient 3).
D: An adjacent section to C, showing complete abscence of α-smooth muscle actin immunoreactivity in the media.
C, D: original magnification, × 100.

adventitia as well. As the amount of amyloid deposition increased, the deposits extended more to partof the media and eventually to the whole vessel
wall, which were clearly demonstrated as absenceof smooth muscle actin immunoreactivity in themedia (Figs. 2C and D). Early small amyloid deposits were never observed in the vicinity of the endothelium or the internal elastic lamina.

The relationship of PPs to SPs and CAAs
In AD patients, there were many mature plaques not
only in the neuropil but also around blood vessels or
adjacent to PPs, but diffuse plaques were not associated with blood vessels. There was no correlation
between the number of PPs and that of SPs, but agood correlation was noted between the number ofPPs and CAAs in AD and CAA patients (Table 2).

14

Immunohistochemistry of perivascular plaqueAβ was deposited initially in periarterial interstitial
fluid drainage pathways of the cerebral cortex andcontributed to CAAs in AD (Weller et al., 1998,2000; Yow et al., 2002). Our results support thishypothesis from 2 aspects. First, PPs were also
found around non-CAA arteries in AD and CAA
patients, although they were frequently seen aroundvarying degrees of CAAs. This finding suggeststhat the formation of PPs precedes the developmentof CAAs. Second, the main component of Aβ in
PPs was Aβ42, and the early Aβ deposits in the vascular wall was also Aβ42, suggesting that Aβ in thevascular wall came from PPs, which was subsequently followed by Aβ40. Yamaguchi et al. (1992)
also reported the same results in an immunoelectron
microscopic study. In addition, Frautschy et al.
(1992) also supported the hypothesis from their observations in animal experiments where direct injection into rat brains of isolated amyloid plaquecores had migrated to vessel walls and ventricularlinings, implying that the distribution of injectedamyloid is not necessarily comparable to the initialsite of its deposition. Our 2 findings, together withother previous reports, were consistent with the Aβ
deposit pathway described by Weller et al. (1998,2000).
In summary, the present study demonstrated
some immunohistochemical characteristics of PPs:
they are immunopositive for Aβ42 and Aβ40,predominant for Aβ42, and always associated withdegenerated neurites and reactive astrocytosis.
These findings suggest that PPs were another formof mature plaque and that they may contribute to thedevelopment of dementia, particularly in CAA-D,and to the formation of CAAs.

Discussion
Uematsu (1923) first described PPs as a perivascular form of SPs. Thereafter Scholz (1938) described
PPs as drusige Entartung in German, SP-like angiopathy in English. He reported the small argyrophilic material resembling SPs initially deposits atthe outer part of the media of the cortical arteries,
extends to the adventitia and then eventually to theperivascular brain tissues. After Scholz, there havebeen few studies focusing on PPs and the neuropathological significance of PPs has not yet been
elucidated.
In this immunohistochemical study, we found
PPs were also a common form of Aβ deposits likeSPs and CAAs in AD and CAA patients. They werealways immunostained with Aβ42 and Aβ40, but
their positive-staining areas were always larger inAβ42 staining. In addition, they were always associated with AT8-positive, degenerated neurites andalso with GFAP-positive astrocytes and astrocytic
fibers within and around them. All of these immunohistochemical features are the same as mature
SPs, indicating that PPs are another form of matureplaque.
PPs were much more frequent in CAA, particularly in CAA-D in which CAAs were remarkably
numerous but the number of both NFTs and SPs
was within range of physiological aging. Furthermore, our semiquantitative analysis revealed nocorrelation between the number of PPs and that ofSPs but a good correlation between the number of
PPs and that of CAAs. These findings suggest thatPPs may play an important role in the pathogenesisof dementia, especially in CAA-D, and that there isa close relationship between the formation of PPs
and the development of CAAs.
Neither the exact origin of Aβ in PPs and CAAs
nor the mechanism by which it is deposited has as
yet been resolved. Mandypur (1975) described thatamyloid appeared in the neuropil along arterioles orin the Virchow-Robin spaces in the cerebral cortex,
but the vessel wall itself was not necessarily involved. Some recent studies raised the hypothesis that

Acknowledgments: The authors thank Professor Kenji
Nakashima, Department of Neurology, Institute of Neurological Sciences, and Professor Ryuzo Kawahara, Division of Neuropsychiatry, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori
University Faculty of Medicine, for their critical readingof the manuscript.

15C. H. Yang et al.

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Corresponding author: Eisaku Ohama, MD, PhD

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