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• W1594119953 abstract "Cerebral amyloid angiopathy in Alzheimer's disease is characterized by deposition of amyloid β (Aβ) in cortical and leptomeningeal vessel walls. Although it has been suggested that Aβ is derived from vascular smooth muscle, deposition of Aβ is not seen in larger cerebral vessel walls nor in extracranial vessels. In the present study, we examine evidence for the hypothesis that Aβ is deposited in periarterial interstitial fluid drainage pathways of the brain in Alzheimer's disease and that this contributes significantly to cerebral amyloid angiopathy. There is firm evidence in animals for drainage of interstitial fluid from the brain to cervical lymph nodes along periarterial spaces; similar periarterial channels exist in humans. Biochemical study of 6 brains without Alzheimer's disease revealed a pool of soluble Aβ in the cortex. Histology and immunocytochemistry of 17 brains with Alzheimer's disease showed that Aβ accumulates five times more frequently around arteries than around veins, with selective involvement of smaller arteries. Initial deposits of Aβ occur at the periphery of arteries at the site of the putative interstitial fluid drainage pathways. These observations support the hypothesis that Aβ is deposited in periarterial interstitial fluid drainage pathways of the brain and contributes significantly to cerebral amyloid angiopathy in Alzheimer's disease. Cerebral amyloid angiopathy in Alzheimer's disease is characterized by deposition of amyloid β (Aβ) in cortical and leptomeningeal vessel walls. Although it has been suggested that Aβ is derived from vascular smooth muscle, deposition of Aβ is not seen in larger cerebral vessel walls nor in extracranial vessels. In the present study, we examine evidence for the hypothesis that Aβ is deposited in periarterial interstitial fluid drainage pathways of the brain in Alzheimer's disease and that this contributes significantly to cerebral amyloid angiopathy. There is firm evidence in animals for drainage of interstitial fluid from the brain to cervical lymph nodes along periarterial spaces; similar periarterial channels exist in humans. Biochemical study of 6 brains without Alzheimer's disease revealed a pool of soluble Aβ in the cortex. Histology and immunocytochemistry of 17 brains with Alzheimer's disease showed that Aβ accumulates five times more frequently around arteries than around veins, with selective involvement of smaller arteries. Initial deposits of Aβ occur at the periphery of arteries at the site of the putative interstitial fluid drainage pathways. These observations support the hypothesis that Aβ is deposited in periarterial interstitial fluid drainage pathways of the brain and contributes significantly to cerebral amyloid angiopathy in Alzheimer's disease. Amyloid β (Aβ) peptides accumulate in the brains of patients with Alzheimer's disease (AD) in senile plaques and in vessel walls as cerebral amyloid angiopathy (CAA). Neither the exact origin of Aβ in plaques and vessel walls nor the mechanism by which it is deposited has, as yet, been resolved. One widely accepted view with regard to CAA is that Aβ in vessel walls is derived from vascular smooth muscle cells,1Wisniewski HM Wegiel J Kotula L Some neuropathological aspects of Alzheimer disease and its relevance to other disciplines.Neuropathol Appl Neurobiol. 1996; 22: 3-11Crossref PubMed Scopus (74) Google Scholar, 2Vinters HV Wang ZZ Secor DL Brain parenchymal and microvascular amyloid in Alzheimer's disease.Brain Pathol. 1996; 6: 179-195Crossref PubMed Scopus (156) Google Scholar but this does not explain why CAA rarely involves larger intracranial arteries or why Aβ does not accumulate in the walls of extracranial vessels.3Shinkai Y Amyloid β-proteins 1-40, and 1-42(43) in the soluble fraction of extra-, and intracranial blood vessels.Ann Neurol. 1995; 38: 421-428Crossref PubMed Scopus (114) Google Scholar In the present study, we challenge the view that Aβ in CAA is derived solely from smooth muscle cells; we then examine the evidence that Aβ is deposited in the periarterial pathways along which interstitial fluid (ISF) drains from the cerebral cortex, and that this contributes significantly to CAA in AD. There is now firm evidence that ISF from the brain drains to regional cervical lymph nodes in a range of species from rodents to sheep.4Cserr HF Harling-Berg CJ Knopf PM Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance.Brain Pathol. 1992; 2: 269-276Crossref PubMed Scopus (343) Google Scholar, 5Boulton M Young A Hay J Armstrong D Flessner M Schwartz M Johnston M Drainage of CSF through lymphatic pathways and arachnoid villi in sheep: measurement of 125I-albumin clearance.Neuropathol Appl Neurobiol. 1996; 22: 325-333Crossref PubMed Scopus (99) Google Scholar, 6Brinker T Lüdemann W Berens von Rautenfeld D Samii M Dynamic properties of lymphatic pathways for the absorption of cerebrospinal fluid.Acta Neuropathol. 1997; 94: 493-498Crossref PubMed Scopus (74) Google Scholar Injections of tracers into the rat brain show that ISF drains along perivascular spaces around intracortical and leptomeningeal arteries; these channels eventually connect with nasal lymphatics at the cribriform plate of the ethmoid bone.4Cserr HF Harling-Berg CJ Knopf PM Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance.Brain Pathol. 1992; 2: 269-276Crossref PubMed Scopus (343) Google Scholar, 7Szentistvanyi I Patlak CS Ellis RA Cserr HF Drainage of interstitial fluid from different regions of the rat brain.Am J Physiol. 1984; 246: F835-F844PubMed Google Scholar, 8Zhang ET Richards HK Kida S Weller RO Directional and compartmentalised drainage of interstitial fluid and cerebrospinal fluid from the rat brain.Acta Neuropathol. 1992; 83: 233-239Crossref PubMed Scopus (180) Google Scholar, 9Kida S Pantazis A Weller RO CSF drains directly from the subarachnoid space into nasal lymphatics in the rat: anatomy, histology and immunological significance.Neuropathol Appl Neurobiol. 1993; 19: 480-488Crossref PubMed Scopus (401) Google Scholar The immunological significance of ISF drainage to cervical lymph nodes is emphasized by experiments in the rat showing that cervical lymphadenectomy reduces both B-cell immune reactions to antigens draining from the brain10Harling-Berg CJ Knopf PM Merriam J Cserr HF Role of the cervical lymph nodes in the systemic humoral immune response to human serum albumin microinfused into rat cerebrospinal fluid.J Neuroimmunol. 1989; 25: 185-193Abstract Full Text PDF PubMed Scopus (152) Google Scholar, 11Knopf PM Cserr HF Nolan SC Wu T-Y Harling-Berg CJ Physiology and immunology of lymphatic drainage of interstitial and cerebrospinal fluid from the brain.Neuropathol Appl Neurobiol. 1995; 21: 175-180Crossref PubMed Scopus (105) Google Scholar and T cell-mediated immune responses in the brain.12Phillips MJ Weller RO Kida S Iannotti F Focal brain damage enhances experimental allergic encephalomyelitis in brain and spinal cord.Neuropathol Appl Neurobiol. 1995; 21: 189-200Crossref PubMed Scopus (41) Google Scholar, 13Weller RO Engelhardt B Phillips MJ Lymphocyte targeting of the central nervous system: a review of afferent and efferent CNS-immune pathways.Brain Pathol. 1996; 6: 275-288Crossref PubMed Scopus (194) Google Scholar, 14Phillips MJ Needham M Weller RO Role of cervical lymph nodes in autoimmune encephalomyelitis in the Lewis rat.J Pathol. 1997; 182: 457-464Crossref PubMed Scopus (97) Google Scholar Periarterial pathways, homologous with ISF drainage pathways in the rat, have been identified by histological and ultrastructural studies in the human brain.15Zhang ET Inman CBE Weller RO Interrelationships of the pia mater and perivascular (Virchow-Robin) spaces in the human cerebrum.J Anat. 1990; 170: 111-123PubMed Google Scholar, 16Kida S Ellison DW Steart PV Weller RO Characterisation of perivascular cells in astrocytic tumours and oedematous brain.Neuropathol Appl Neurobiol. 1995; 21: 121-129Crossref PubMed Scopus (12) Google Scholar, 17Weller RO Fluid compartments and fluid balance in the central nervous system.in: Williams PL Gray's Anatomy. ed 38. Churchill Livingstone, Edinburgh1995: 1202-1224Google Scholar, 18Pollock H Hutchings M Weller RO Zhang E-T Perivascular spaces in the basal ganglia of the human brain: their relationship to lacunes.J Anat. 1997; : 337-346Crossref PubMed Google Scholar In the human cerebral cortex, periarterial spaces are encompassed by an outer sheath of leptomeningeal cells derived from the pia mater, and these spaces are in direct continuity with perivascular spaces around arteries in the subarachnoid space.15Zhang ET Inman CBE Weller RO Interrelationships of the pia mater and perivascular (Virchow-Robin) spaces in the human cerebrum.J Anat. 1990; 170: 111-123PubMed Google Scholar, 17Weller RO Fluid compartments and fluid balance in the central nervous system.in: Williams PL Gray's Anatomy. ed 38. Churchill Livingstone, Edinburgh1995: 1202-1224Google Scholar In the basal ganglia, the arrangement is slightly different, as periarterial spaces are lined both on the inner and the outer aspects by layers of leptomeninges; however, the periarterial spaces within the brain are still in continuity with the perivascular spaces of leptomeningeal arteries.18Pollock H Hutchings M Weller RO Zhang E-T Perivascular spaces in the basal ganglia of the human brain: their relationship to lacunes.J Anat. 1997; : 337-346Crossref PubMed Google Scholar No such well defined continuity of intracortical and leptomeningeal perivascular spaces has been observed in relation to veins.15Zhang ET Inman CBE Weller RO Interrelationships of the pia mater and perivascular (Virchow-Robin) spaces in the human cerebrum.J Anat. 1990; 170: 111-123PubMed Google Scholar Reports of glioblastoma metastasizing from the brain to cervical lymph nodes19Campora RG Salaverri CO Ramirez FV Villaddiego MS Davidson HG Metastatic glioblastoma multiforme in cervical lymph nodes: report of a case with diagnosis by fine needle aspiration.Acta Cytologica. 1993; 37: 938-942PubMed Google Scholar suggest that they may act as regional lymph nodes for the brain in humans as in other mammals. Evidence that smooth muscle cells are a source of vascular amyloid1Wisniewski HM Wegiel J Kotula L Some neuropathological aspects of Alzheimer disease and its relevance to other disciplines.Neuropathol Appl Neurobiol. 1996; 22: 3-11Crossref PubMed Scopus (74) Google Scholar, 20Wisniewski HM Wegiel J β-Amyloid formation by myocytes of leptomeningeal vessels.Acta Neuropathol. 1994; 87: 233-241Crossref PubMed Scopus (155) Google Scholar derives mainly from the observations that they contain β-amyloid precursor protein (APP) fragments21Kawai M Degeneration of vascular muscle cells in cerebral amyloid angiopathy of Alzheimer's disease.Brain Res. 1993; 623: 142-146Crossref PubMed Scopus (176) Google Scholar and that they lie immediately adjacent to vascular Aβ deposits. However, there are a number of problems with accepting that smooth muscle cells are the sole source of Aβ in CAA. First, CAA is strictly confined to the central nervous system in AD, and extracranial vessels are free of Aβ deposits,3Shinkai Y Amyloid β-proteins 1-40, and 1-42(43) in the soluble fraction of extra-, and intracranial blood vessels.Ann Neurol. 1995; 38: 421-428Crossref PubMed Scopus (114) Google Scholar but there is little evidence that smooth muscle cells in extracranial arteries differ from intracranial arteries in terms of APP metabolism.3Shinkai Y Amyloid β-proteins 1-40, and 1-42(43) in the soluble fraction of extra-, and intracranial blood vessels.Ann Neurol. 1995; 38: 421-428Crossref PubMed Scopus (114) Google Scholar Second, if Aβ were produced by smooth muscle cells, early deposits of amyloid would be located throughout the tunica media, rather than in the adventitia and outer media.20Wisniewski HM Wegiel J β-Amyloid formation by myocytes of leptomeningeal vessels.Acta Neuropathol. 1994; 87: 233-241Crossref PubMed Scopus (155) Google Scholar, 21Kawai M Degeneration of vascular muscle cells in cerebral amyloid angiopathy of Alzheimer's disease.Brain Res. 1993; 623: 142-146Crossref PubMed Scopus (176) Google Scholar, 22Yamaguchi H Beta amyloid is focally deposited within the outer basement membrane in the amyloid angiopathy of Alzheimer's disease: an immunoelectron microscopic study.Am J Pathol. 1992; 141: 249-259PubMed Google Scholar Third, if vascular smooth muscle cells were the only or major source of Aβ, it would be expected that the larger arteries would be more prone to CAA, as they contain more smooth muscle cells, but, in fact, they are less severely involved than the smaller arteries.3Shinkai Y Amyloid β-proteins 1-40, and 1-42(43) in the soluble fraction of extra-, and intracranial blood vessels.Ann Neurol. 1995; 38: 421-428Crossref PubMed Scopus (114) Google Scholar In the present study to test the hypothesis that Aβ is deposited in periarterial ISF drainage pathways of the brain in AD, we use both biochemical and histological methods. Biochemical techniques are used to show that there is a pool of soluble Aβ in non-AD cerebral cortex, which is presumably eliminated continuously from the normal brain. Qualitative and quantitative histological and immunohistochemical techniques are used to demonstrate 1) that there is a correlation between the presence of Aβ senile plaques in the brain and amyloid angiopathy in AD; 2) that insoluble Aβ accumulates selectively around small arteries in the brain and leptomeninges with relative sparing of large arteries and veins, suggesting that deposition of Aβ occurs in drainage pathways nearest the site of origin of Aβ from the brain; and 3) that small and possibly the earliest deposits of Aβ in the walls of leptomeningeal arteries occur at the site of putative ISF fluid drainage pathways in the adventitia, and that only later does Aβ accumulate in the tunica media. Biochemical quantitation of soluble Aβ was performed on cerebral cortex from six brains of clinically nondemented control cases without a history of neurological disease (average age, 79 years; range, 69–92 years) selected from the Sun Health Research Institute brain bank. All six cases had a ε3/ε3 apolipoprotein E (ApoE) genotype. On histological (thioflavin S and Campbell-Zwitzer stains) and immunocytochemical (4G8, 10D5, and ubiquitin antibodies) examination, these brains showed no visible deposits of amyloid in the parenchyma or in the vasculature and no neurofibrillary tangles. Quantitative and qualitative studies of senile plaques and CAA were performed on 17 formalin-fixed AD brains; 7 were from the Sun Health Research Institute brain bank, and 10 were from the Neuropathology Laboratory, University of Southampton. Tris-hydroxymethyl aminomethane (Tris), ethylenediaminetetraacetic acid, leupeptin, pepstatin, phenylmethylsulfonyl fluoride, phenanthroline, benzamidine, and thioflavin S were from Sigma Chemical Co. (St. Louis, MO). Gentamicin sulfate, amphotericin B, hydrochloric acid, and formic acid were obtained from Fluka Chemie AG (Buchs, Switzerland). On all occasions, formic acid was glass distilled in our laboratory before use. Antibody 4G8 (against Aβ17–24) was obtained from Senetek (Maryland Heights, MO) and was labeled with europium according to the manufacturer's procedure (Wallac Inc., Gaithersburg, MD). Eu and enhancement solution were from Delfia (Wallac, Inc.). Polyclonal antibodies R163 and R165 specifically raised against Aβ40 and Aβ42, respectively, were obtained from Dr. P. Mehta of the New York State Institute for Brain Research (Staten Island, NY). These antibodies do not exhibit cross-reactivity between each other up to 50 ng/ml. For immunocytochemistry on paraffin sections, an antibody raised against Aβ1-39/42 was kindly donated by Dr. C. Wischik of the MRC Laboratory for Molecular Biology (Cambridge, UK). Cerebral cortex (0.8 g) from the superior frontal gyrus was carefully separated from the underlying white matter. The tissue was minced into fine pieces and, to remove unwanted blood, rinsed three times with 5 ml of protease inhibitor buffer (20 mmol/L Tris-HCl, pH 8.5, 3 mmol/L ethylenediaminetetraacetic acid, 500 μg/L leupeptin, 700 μg/L pepstatin, 35 mg/L phenylmethylsulfonyl fluoride, 100 mg/L 1,10 phenanthroline, 100 mg/L benzamidine, 50 mg/L gentamicin sulfate, and 250 μg/L amphotericin B). The tissue was thoroughly homogenized with a motorized Duall tissue grinder (100 μm clearance) in the presence of 3 ml of the above buffer. The brain homogenates, 4 ml per sample, were spun at 100,000 × g for 1 hour at 4°C. The supernatants and pellets were collected and stored separately. For Aβ quantitation, polyclonal antibodies R163 and R165 were coated to the wells of microtiter plates and used as the capture antibodies. Bovine serum albumin (1%) in TTBS (0.05% Tween in 20 mmol/L Tris-HCl and 0.5 mol/L NaCl, pH 7.4) was used as blocking solution. One hundred μl of the supernatant or of Aβ standards was applied to the wells and allowed to stand at room temperature for 2 hours on a rocking platform. The unbound materials were removed by washing the plate three times with TTBS. Europium-labeled 4G8 was added to the wells and incubated for 2 hours followed by four washes with TTBS and two washes with deionized water. Finally, the Eu-enhancement solution was added to each well and the plates were read in a fluorimeter using excitation and emission wavelengths of 320 and 615 nm, respectively. The values, obtained from triplicated wells, were calculated based on standard curves generated on each plate. A total of 24 blocks of cerebral cortex were taken from 3 AD brains. From each brain, two blocks were taken from frontal, temporal, parietal, and occipital lobes. The leptomeningeal vessels were carefully stripped from the surface of the blocks of brain, stained free floating with thioflavin S, and spread onto glass slides for observation in either ultraviolet light (395 nm) or visible light (450 nm). Aβ deposition in leptomeningeal vessels was recorded on a semiquantitative scale in these preparations: −, no evidence of amyloid; +, moderate amyloid deposition and no aneurysm formation on the vessels; ++, clear evidence of amyloid angiopathy and some vessels with occasional aneurysm formation; +++, obvious amyloid angiopathy in the majority of vessels; and ++++, virtually all vessels showing evidence of amyloid angiopathy and multiple aneurysms. Blocks of cerebral cortex from which the leptomeninges had been stripped were dehydrated and embedded in paraffin, and 5-μm sections were stained with thioflavin S. The total number of thioflavin S-positive amyloid plaques in the gray matter on each slide (mean area, 30 mm2) was counted and the number of plaques per unit area of cortex (plaque density) was estimated using Color Vision version 1.7.4.A on an Apple Macintosh Quadra 700 computer. The semiquantitative estimation of thioflavin S-stained amyloid deposition in the leptomeningeal vessels was compared with the plaque density in the underlying cortex. A total of 56 blocks of cerebral cortex were taken from seven AD brains. Two blocks were taken from the frontal, temporal, parietal, and occipital cortex of each brain. Leptomeningeal vessels were carefully stripped from the brain's surface and histologically processed, sectioned (5 μm), and stained with thioflavin S. A total of 681 arteries and 352 veins were investigated. For immunocytochemical studies, 5-μm sections were stained with an antibody against Aβ1-39/42. The number of diffuse and fibrillar plaques in the entire cortical area of each section was counted using a Leitz Laborlux K light microscope with a ×20 objective lens. The area of gray matter was measured in serial sections stained with the hematoxylin van Gieson technique using enhanced image analysis. Cortical plaque densities were calculated for each plaque type by dividing the relevant plaque count by the area of gray matter analyzed. Assessment of amyloid angiopathy was performed on paraffin sections of leptomeningeal vessels stained with thioflavin S and examined in ultraviolet light under a fluorescence microscope. All vessels that had been sectioned transversely (ie, at no point was the maximum diameter more than twice the minimum diameter) were assessed. The diameter of each vessel was recorded using an eyepiece graticule. Identification of vessels as arteries and veins depended on the ratio of wall thickness to lumen diameter and the presence or not of an elastic lamina. Five brains from patients with AD were used for the isolation of intracortical and leptomeningeal vessels for qualitative assessment of the deposition of amyloid. Cerebral cortex from all four cerebral lobes were cut into approximately 1-cm3 pieces and lysed in 20 volumes of 15% sodium dodecyl sulfate, prepared in 50 mmol/L Tris-HCl (pH 7.5) buffer containing 5 mmol/L ethylenediaminetetraacetic acid. After 72 hours of continuous stirring and two changes of sodium dodecyl sulfate, the remaining tufts of blood vessels were filtered out, washed with buffer, and stained with thioflavin S. Leptomeningeal vessels, stripped from the surface of cerebral cortex, were spread on glass slides, air dried, stained with thioflavin S, and examined in a fluorescence microscope by phase contrast and by Nomarski optics. Selected vessels were examined with a Leica TCS4D Krypton-Argon confocal laser scanning microscope; the image of thioflavin S fluorescence under light of 490-nm wavelength was digitally captured in 64 planes, allowing three-dimensional reconstruction. Cerebral cortex from three AD brains was taken fresh postmortem, fixed in glutaraldehyde, postfixed in osmium, stained with uranyl acetate, and embedded in Epon Araldite resin for electron microscopy. Thin sections of cerebral cortex were stained with lead citrate and examined in a Phillips 400 transmission electron microscope. In the six brains from clinically nondemented control cases, Europium immunoassay demonstrated an average value of water-soluble Aβ of 2.75 ng/g of cerebral cortex (range, 0.2 to 8.6 ng/g). In only one instance was the level of water-soluble Aβ below the detection limit of 0.1 ng/g. Although this level is in contrast to the average of 36.8 ng/g of water-soluble Aβ in AD brains that we have previously demonstrated,23Kuo Y-M Emmerling MR Vigo-Pelfrey C Kasunic TC Kirkpatrick JB Murdoch GH Ball MJ Roher AE Water-soluble Aβ (N-40, N-42) oligomers in normal, and Alzheimer disease brains.J Biol Chem. 1996; 271: 4077-4081Crossref PubMed Scopus (556) Google Scholar it nevertheless shows that Aβ is present in a water-soluble pool of non-AD brain tissue without visible deposits of Aβ. Detailed examination of thioflavin S-stained sections of brain and overlying meninges stripped from the cerebral cortex showed that amyloid angiopathy did not occur in the absence of amyloid deposition in senile plaques in the underlying cortex. A positive correlation between the degree of amyloid angiopathy and the deposits of fibrillar amyloid in the subjacent cortex was observed up to the +++ levels of CAA (P < 0.05; Table 1). However, this increase was not maintained with the grade ++++ CAA.Table 1Degree of Amyloid Angiopathy in Leptomeningeal Vessels Compared with Density of Fibrillar Amyloid Plaques in the Underlying Cortex: Thioflavin S.Severity of amyloid angiopathyPlaques per mm2 cortex ±SDThioflavin S-stained plaques were up to 100 times less numerous than those identified by Aβ immunocytochemistry.−*No amyloid angiopathy.0.00+0.23 ± 0.27++0.7 ± 0.4+++1.04 ± 0.5†The mean density of plaques in the cortex underlying vessels with grade +++ amyloid angiopathy is significantly higher than plaque density with no (−), +, and ++ grades of amyloid angiopathy (P = 0.05).++++0.33 ± 0.34* No amyloid angiopathy.† The mean density of plaques in the cortex underlying vessels with grade +++ amyloid angiopathy is significantly higher than plaque density with no (−), +, and ++ grades of amyloid angiopathy (P = 0.05).†† Thioflavin S-stained plaques were up to 100 times less numerous than those identified by Aβ immunocytochemistry. Open table in a new tab In a parallel study in which senile plaques were immunocytochemically stained, a significant correlation between the number of plaques in the cerebral cortex and the extent of CAA in the overlying meninges, detected by thioflavin S, was observed in four of seven cases (P < 0.05). The r values in these cases ranged from 0.6697 to 0.9139 with a mean of 0.7817. In the other three cases examined, no such correlation was observed, except that CAA did not occur in the absence of amyloid plaques in the associated cortex. In paraffin sections of leptomeninges stained with thioflavin S, amyloid deposition was detected in the walls of 20.2% of 681 arteries and in 4.5% of 352 veins (Table 2). This represents a ratio of 5:1 for amyloid deposition in the walls of arteries compared with veins. Deposition of amyloid in arterial walls was observed in 24.7% of small leptomeningeal arteries (less than 60 μm in diameter) and in 11.2% of larger arteries (60 to 300 μm in diameter), giving a ratio of 2:1 between the two groups. No difference in the degree of amyloid deposition between veins of large and small diameter was seen. Amyloid deposition in intracortical vessels followed a similar pattern to that observed in the leptomeninges with arteries predominating over veins.Table 2Amyloid Deposition in Leptomeningeal Vessels: Thioflavin S StainNature of vesselsNumber countedProportion of vessels positive for amyloidTotal arteries68120.3%Total veins3524.4%Arteries <60 μm in diameter45824.7%Arteries >60 μm in diameter22311.2%Veins <60 μm in diameter1934.5%Veins >60 μm in diameter1594.2% Open table in a new tab Treatment of cerebral cortex from brains of patients with AD with 10% SDS resulted in isolation of the blood vessels; vessel basement membranes, perivascular connective tissue, and amyloid deposits were preserved, because these structures are insoluble in the detergent. Thioflavin S-stained preparations revealed globular deposits of amyloid arranged like beads along small blood vessels (Figure 1A) with linear deposits of amyloid outlining the intervening blood vessel walls (Figure 1B). Arteries of larger diameter within the cortex contained band-like deposits of amyloid distributed transversely, or circumferentially around the vessel wall (Figure 1C). Immunocytochemistry for Aβ in paraffin sections showed that the band-like disposition of the amyloid was due to the interposition of smooth muscle cells between the Aβ deposits (Figure 1D); preserved smooth muscle cells were clearly seen surrounded by Aβ. At the surface of the brain, Aβ was observed in the walls of arteries as they penetrated the cortex, in leptomeningeal arteries, and deposited at the glia limitans (Figure 1D). Electron microscopy of intracortical arteries showed deposition of amyloid within dilated perivascular spaces separating the glia limitans from the apparently intact vessel wall (Figure 2A). In other arteries, amyloid was deposited between smooth muscle cells with considerable disruption of the vessel wall (Figure 2B). Thin profiles of smooth muscle were observed within the amyloid, and smooth muscle cells in the subintimal region appeared to be better preserved than those in the outer aspects of the wall (Figure 2B). The pattern of Aβ deposits in the walls of leptomeningeal arteries was similar to that in the larger intracortical arteries. Bands of amyloid were disposed intermittently along the length of arteries, often concentrated distal to bifurcations (Figure 3A). In areas where amyloid deposition was heavy, aneurysm formation occurred either as fusiform expansion of the vessel (Figure 3A) or as more saccular extrusions (Figure 3B). In some instances, the microaneurysms were surrounded by fine deposits of hemosiderin, suggesting past hemorrhage. Paraffin sections stained with thioflavin S revealed patchy deposition of amyloid in the small leptomeningeal arteries; either the whole thickness of the artery wall was involved or amyloid was completely absent (Figure 3C). Small deposits of Aβ in the larger leptomeningeal arteries were always at the periphery of the tunica media where it meets the adventitia close to the periarterial space (Figure 3, C and D). Early deposits of amyloid were never observed in the vicinity of the endothelium or the internal elastic lamina. As the amount of amyloid increased, deposits involved the outer part of the media in addition to the more peripheral regions of the artery wall (Figure 3, E and F). Occasionally, small deposits of amyloid were present in the connective tissue of the arachnoid mater (Figure 3D), but they were always extremely small in comparison with deposits in arterial walls. Deposition of amyloid in leptomeningeal veins was much less common than in arteries (Table 2) and very small in amount. The results of the present study suggest that Aβ peptides are produced by neural tissue and drain with ISF along periarterial pathways which, by analogy with other species,4Cserr HF Harling-Berg CJ Knopf PM Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance.Brain Pathol. 1992; 2: 269-276Crossref PubMed Scopus (343) Google Scholar, 24Weller RO Kida S Zhang E-T Pathways of fluid drainage from the brain: morphological aspects and immunological significance.Brain Pathol. 1992; 2: 227-284Crossref Scopus (241) Google Scholar are the lymphatic drainage pathways of the human brain.15Zhang ET Inman CBE Weller RO Interrelationships of the pia mater and perivascular (Virchow-Robin) spaces in" @default.
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• W1594119953 date "1998-09-01" @default.
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• W1594119953 title "Cerebral Amyloid Angiopathy" @default.
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• W1594119953 doi "https://doi.org/10.1016/s0002-9440(10)65616-7" @default.
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