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(Stroke. 1997;28:1423-1429.)
© 1997 American Heart Association, Inc.

Articles

Alterations in Glia and Axons in the Brains of Binswanger's Disease Patients

Ichiro Akiguchi, MD; Hidekazu Tomimoto, MD; Toshihiko Suenaga, MD; Hideaki Wakita, MD; Herbert Budka, MD

From the Department of Neurology, Faculty of Medicine, Kyoto University, Kyoto 606 Japan (I.A., H.T., T.S., H.W.), and the Institute of Neurology, University of Vienna, A-1097 Wien, Austria (H.B.).

Correspondence to I. Akiguchi, MD, Department of Neurology, Faculty of Medicine, Kyoto University, Kyoto 606 Japan.

	Abstract

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Background and Purpose Although increasing attention is being paid to Binswanger's disease, a form of vascular dementia characterized by diffuse white matter lesions, only limited information is available on the pathological changes that occur in the glia and axons in the white matter. We therefore investigated the brains of patients with Binswanger's disease to gain further insight into its pathophysiology.

Methods Autopsied brains from patients with Binswanger's disease (group 3; n=17) were compared with those of non-neurological controls (group 1; n=5) and controls with large cortical infarcts but without significant white matter lesions (group 2; n=5). Glial fibrillary acidic protein (GFAP) was used as an immunohistochemical marker for astroglia, leukocyte common antigen (LCA) was used as a marker for microglia, and HLA-DR was used as a marker for activated microglia. Axonal damage was assessed by the accumulation of proteins, which are transported by fast axonal flow, amyloid protein precursor (APP), synaptophysin, and chromogranin A.

Results Although there was no difference in numerical density of GFAP-immunoreactive astroglia in each group, regressive astroglia were observed in 7 of 17 patients with Binswanger's disease. LCA-immunoreactive microglia were 1.7 times more numerous in Binswanger's disease than in group 1 (P<.05). HLA-DR–immunoreactive–activated microglia were 3.4 times and 2.1 times more numerous in Binswanger's disease as compared with group 1 (P<.01) and group 2 (P<.05), respectively. There was frequent perivascular lymphocyte cuffing, and clusters of macrophages with a decreased number of oligodendroglia were observed in the rarefied white matter. The grading scores for the number of axons immunoreactive for either APP, synaptophysin, or chromogranin A were significantly higher in Binswanger's disease than in group 1 or 2.

Conclusions The pathological alterations in Binswanger's diseased brains include regressive changes in the astroglia and activation of the microglia with a decrease in the oligodendroglia, which were associated with the degradation of both myelin and axonal components. These results indicate that an inflammatory reaction and compromised axonal transport, mediated by chronic ischemia, may play an important role in the pathophysiology of Binswanger's disease.

Key Words: white matter • Binswanger's disease • astrocytes • microglia

	Introduction

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In recent reviews, it has been demonstrated that vascular dementia consists of a number of heterogeneous pathological conditions.^{1 2 3} Multi-infarct dementia (MID), which is characterized by multiple cortical infarcts, is not the only category of vascular dementia; small artery disease, characterized by multiple lacunar infarcts, is another important type of vascular dementia.

There seem to be significant regional differences in the prevalence rates of these categories, with MID being more prevalent in North American countries.⁴ In Japan, multiple lacunar infarcts are the leading cause of vascular dementia.⁵ Binswanger's disease, a combination of diffuse WM lesions and subcortical lacunar infarcts, is also relatively common; it is found in 3.8% of elderly patients at autopsy.⁶ Recent diagnostic criteria for vascular dementia refer to Binswanger's disease,^{7 8 9} and increasing attention has been paid to Binswanger's disease not only in European countries and Japan but also in North American countries.^{3 7 10 11} WM lesions, which are the pathological hallmark of Binswanger's disease, are also frequently found in other types of vascular dementia and Alzheimer's disease.^{12 13} They are correlated with cerebral hypoperfusion¹⁴ and are related to impaired cognitive and lower extremity function.^{15 16 17 18}

In radiological-pathological correlation studies, WM lesions found on CT or MRI scans were usually found to correspond to heterogeneous conditions, including incomplete infarction, état criblé, perivascular demyelination, and gliosis.^{19 20 21} However, WM lesions may also correspond to the normal WM in some patients.²²

In brains with ischemic cerebral infarction, we have demonstrated that cerebrovascular WM lesions are associated with compromised axonal transport^{23 24} and blood-brain barrier function.²⁵ In addition, there are regressive changes in the astroglia²⁶ and frequent infiltration of T lymphocytes and activated microglia.^{23 27} However, only limited information is available on the pathological aspects of Binswanger's disease. In previous studies, the most vulnerable cellular component was myelin,^{13 28 29} but the axonal cylinder was also involved.³⁰

The purpose of the present study was to document the pathological alterations in the glia and axons in Binswanger's diseased brains from both Japanese and Austrian patients and to further determine whether these changes are common to cerebrovascular WM lesions resulting from other causes. Brains with clinicopathologically proven Binswanger's disease were immunohistochemically examined, along with brains from non-neurological patients and brains with large cortical infarcts, both of which were devoid of significant WM lesions. Our results indicate that alterations in the glia and axons in Binswanger's disease were more diffuse and prominent than, but not distinct from, those seen in other ischemic cerebrovascular diseases.

	Materials and Methods

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Patient Profiles
Non-neurological control brains (group 1) were obtained from 2 patients with heart disease, 1 patient with liver cancer, 1 patient with lung cancer, and 1 patient with nephropathy, all of whom had no underlying neurological disease. As neurological controls, 5 patients with large cortical infarcts but with no significant WM lesions were used (group 2). Four patients were in their chronic stage, and one case (No. 6) was a patient who had suffered an embolic occlusion of the middle and posterior cerebral arteries and had died 28 days after the onset (Table 1).

View this table: [in this window] [in a new window]   Table 1. Clinical and Neuropathological Features of the Present Patients

Seventeen brains with Binswanger's disease (13 from the Neuropathology Laboratory at the University of Wien and 4 from Kyoto University) were examined (group 3). The diagnosis of Binswanger's disease was made clinicopathologically and retrospectively met all of the clinical criteria proposed by Bennett et al.⁷ A representative profile is presented as follows.

Patient No. 26 was a 64-year-old widower who died of aspiration pneumonia. He had an irregular diet after a divorce at age 59. In July 1991, he noticed weakness of his right upper extremity and urinary incontinence. On admission, an examination revealed right hemiparesis, a positive right Babinski sign, and generalized hyperreflexia. Neuropsychological testing also revealed impaired cognitive function. His blood pressure was normal. A MRI scan revealed leukoaraiosis and lacunar infarcts in the basal ganglia and white matter (Fig 1). Single-photon emission computed tomography scans showed hypoperfusion in the fronto-temporal regions bilaterally. The patient was given aspirin at 80 mg daily. At 2 months after the onset, his right hemiparesis improved. He had poor memory and concentration but was independent in his daily life. One year after admission, he was believed to be abulic and gradually became incapable of looking after himself. He suffered from recurrent pulmonary and urinary tract infections and became bedridden. He died on December 26, 1995.

View larger version (144K): [in this window] [in a new window]   Figure 1. Magnetic resonance imaging of patient No. 26 performed on Dec 5, 1995. T2-weighted images (A through C) and T1-weighted image (D) at the same level as that seen in panel C. Note diffuse WM lesions (A and B) and lacunar infarcts in the basal ganglia (C and D).

All the brains in groups 1 and 2 had no histological evidence of Alzheimer's disease. There were no significant age differences between the three groups (Table 1).

Tissue Procurement
Brains from the University of Wien were fixed in formalin for 3 to 7 days. Those from Kyoto University were perfusion-fixed in either 4% paraformaldehyde and 0.35% glutaraldehyde or 4% paraformaldehyde in 0.1 mol/L PB, pH 7.4, for 20 minutes, and then post-fixed in 4% paraformaldehyde in 0.1 mol/L PB for 24 to 48 hours. They were sectioned in the coronal plane and embedded in paraffin. The standard histological examination included hematoxylin-eosin staining for general observation, Klüver-Barrera (KB) and Bielschowsky stainings for the assessment of WM lesions, and oil red O staining.

Immunohistochemical Staining
We examined tissue blocks at the anterior tip of the caudate nucleus, which included the cingulate and superior, middle, and inferior frontal gyri. In patients with large cortical infarcts, sections adjacent to the infarcts were excluded. These sections were incubated with a series of primary antibodies diluted in 0.1 mol/L PBS overnight at 4°C. The following antibodies were used in the present study: an anti-GFAP antiserum (Dakoppats, rabbit IgG, diluted 1:200) as a marker for astroglia, an anti-LCA antibody (Dakoppats, mouse IgG, diluted 1:100) as a marker for microglia, an anti–HLA-DR antibody (Dakoppats, mouse IgG, diluted 1:100) as a marker for activated microglia, and anti-CD4 (Nichirei, mouse IgG, diluted 1:50) and anti-CD8 (Nichirei, mouse IgG, diluted 1:50) antibodies as markers for T cells. Although LCA labels not only microglia/macrophage but also blood monocyte, the latter is easily differentiated by its morphological characteristics. Damaged axons were labeled by an antibody against APP (anti-APP592; a rabbit antiserum raised against the recombinant N-terminal 592 residues of an APP fusion protein; a generous gift from Dr Y. Tokushima, Asahi Chemical Industry Co Ltd, 0.05 µg/mL), an anti-synaptophysin (Dakoppats, rabbit IgG, diluted 1:100) antiserum, and an anti-CgA (Dakoppats, rabbit IgG, diluted 1:100) antiserum. The use of axonally transported proteins has been extensively investigated as potential markers for axonal damage.^{23 31}

After incubation with the primary antibodies, the sections were treated with the appropriate biotinylated secondary antibodies (Vector Laboratories, diluted 1:200). These sections were subsequently treated with an avidin biotin complex (ABC, Vector Laboratories, diluted 1:200) and then visualized with 0.01% diaminobenzidine tetrahydrochloride and 0.005% H₂O₂ in 50 mmol/L Tris HCl (pH 7.6). To test for the specificity of the immunohistochemical reaction, control sections were incubated with normal mouse or rabbit IgG and normal rabbit serum instead of the primary antibody.

Morphometry
In the sections stained with KB, the WM lesions were graded as normal (grade 0), low (grade 1), moderate (grade 2), and high (grade 3) according to the criteria proposed by Englund et al.^{25 28} The sections were counterstained with hematoxylin, and the numerical density of GFAP-labeled astroglia, LCA-labeled microglia, and HLA-DR–labeled–activated microglia was examined by counting the number of nuclei with immunopositive perikarya in 20 representative square fields of 0.0625 mm² each. The frequency of damaged axons labeled by either APP, synaptophysin, or CgA was graded as 0 (none), 1 (ungrouped immunopositive fibers without bundle formation), 2 (less than 1 segregated bundle of immunopositive fibers per 1.0 cm²), or 3 (1 or more numerous segregated bundles of immunopositive fibers per 1.0 cm²).

Statistical analysis was performed by nonparametric group tests (Mann-Whitney U test) using StatView II software (Abacus Concepts, Inc) on a Macintosh computer.

	Results

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The mean age did not differ significantly among the groups (Table 1). There were no significant WM lesions in groups 1 and 2. Of the 17 Binswanger's disease patients, 12 were male and 5 were female. Fourteen brains showed grade 3 WM lesions, and 3 showed grade 2 lesions (Table 2).

View this table: [in this window] [in a new window]   Table 2. Numerical Density of Glial Cells and Frequency of Injured Axons in the Brains of Binswanger's Disease Patients

In the control sections stained without the primary antibodies, no specific immunohistochemical staining was observed. Although the numerical density of GFAP-immunoreactive astroglia did not differ significantly among the three groups, some astroglia in the Binswanger's diseased brains showed regressive changes such as nuclear pyknosis, swelling, and vacuolation of the cell bodies as well as disintegration of their processes (Fig 2); this was previously termed clasmatodendrosis.³² In the neuropil there were granular structures, which were believed to be disintegrated astroglial processes. On hematoxylin-eosin staining, these clasmatodendritic astroglia had plump cell bodies but showed modest eosinophilia (photo not shown). These glial cells were present in 7 of 17 patients with Binswanger's disease but were not observed in the brains of groups 1 and 2.

View larger version (131K): [in this window] [in a new window]   Figure 2. Photomicrograph of the immunohistochemistry for GFAP in a Binswanger's diseased brain. The astroglia showed regressive changes such as swelling, vacuolation of the cell bodies, and disintegration of their processes, which were recognizable as granules in the neuropil. The photo was taken in patient No. 17. The bar indicates 50 µm.

The numerical density of the microglia labeled by LCA was 1.7 times greater in the Binswanger's disease group than in group 1. Activated microglia, indicated by their truncated processes and HLA-DR immunoreactivity, were 3.4 times more numerous in the Binswanger's disease group as compared with group 1 (P<.01) and 2.1 times more numerous than in group 2 (P<.05) (Fig 3A, Table 2). The HLA-DR–immunopositive microglia were preferentially distributed in the perivascular regions of the deep WM but were absent in the subcortical WM regions (photo not shown). Lipid-laden macrophages, which can be detected by oil red O staining, were found in clusters in 12 of 17 brains with Binswanger's disease (Fig 3B and 3C, Table 2). In contrast, in the brains of group 1 and group 2 patients, only 2 cases with large cortical infarcts showed macrophage infiltration foci. There were no significant differences in the number of LCA- or HLA-DR–immunolabeled cells between groups 1 and 2. Mononuclear cells, which were observed by KB staining and/or immunohistochemistry for LCA, were found in the perivascular space in 13 of 17 brains with Binswanger's disease and occasionally infiltrated into the neural parenchyma (Fig 3D). Some of these cells were immunolabeled for CD4 and CD8, indicating that they were of the T-cell lineage (photo not shown).

View larger version (96K): [in this window] [in a new window]   Figure 3. Photomicrographs of the immunohistochemistry for HLA-DR (A and B) and LCA (C and D) in Binswanger's diseased brains. Activated microglia with truncated processes (A) and lipid-laden macrophages (B) were immunoreactive for HLA-DR. Clusters of microglia/macrophages were also labeled by LCA (C). Mononuclear cells that were immunoreactive for LCA were localized to the perivascular space but occasionally infiltrated into the neural parenchyma (D). The photos were taken from patient No. 20 (A and B) and patient No. 13 (C and D). The bars indicate 100 µm (A and B) and 200 µm (C and D), respectively.

There was marked accumulation of APP, synaptophysin, and CgA in the axonal bundles in Binswanger's diseased brains (Fig 4A and 4B; not shown for synaptophysin), whereas no patients in group 1 and only one patient in group 2 had accumulated these proteins significantly. APP-immunoreactive glial cells were occasionally associated with these damaged axons (Fig 4C). These damaged axons were accompanied by a decrease in myelin, which was indicated by light myelin staining. A decreased number of oligodendroglial cell nuclei was observed in the regions with severe WM lesions on KB staining (Fig 5).

View larger version (37K): [in this window] [in a new window]   Figure 4. Photomicrographs of the immunohistochemistry for APP (A and C) and CgA (B) in Binswanger's diseased brains. There is an accumulation of APP in the axonal bundles (A) and glial cells (C). The region corresponding to panel A contained CgA-immunoreactive fibers (C). The photos were taken from patient No. 20 (A and B) and patient No. 17 (C). The bars indicate 100 µm.

View larger version (42K): [in this window] [in a new window]   Figure 5. Photomicrographs of Klüver-Barrera staining in a Binswanger's diseased brain. The region indicated by a small asterisk in panel A is shown in panel B under higher magnification, and the region indicated by the large asterisk is shown in panel C. The latter is the region where the APP immunoreactive fibers in Fig. 4A were observed. Note the light myelin staining and decreased number of oligodendroglial nuclei in the deep white matter (B) as compared with the subcortical white matter (C). The photos were taken from patient No. 20. The bars indicate 100 µm.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Previous immunohistochemical and electron microscopic studies from our laboratory have focused on pathological changes in cerebrovascular WM lesions, and only limited information was available on the pathology of Binswanger's disease. In the present study, we demonstrated changes in the microglia and astroglia, as well as compromised axons, in clinicopathologically proven Japanese and Austrian patients of Binswanger's disease.

In a previous study, GFAP-immunolabeled astroglia increased in number in mild cerebrovascular WM lesions; however, there was no such increase in severe WM lesions, and the astroglia occasionally showed regressive changes previously termed clasmatodendrosis.^{25 32} In Binswanger's diseased brains, the numerical density of cells with an astroglial morphology has been reported to be decreased.³³ In the present study, there was no decrease in the number of GFAP-immunoreactive astroglia, but clasmatodendritic astroglia were occasionally observed. Although this morphological transformation of the astroglia may occur as a postmortem artifact,^{34 35} our previous observations of the condensation of the nuclear chromatin and large cytoplasmic inclusion bodies in clasmatodendritic astroglia in WM lesions argue against this.²⁶ It is highly likely that clasmatodendrosis is a response of regressive astroglia to brain edema, since it occurs in various conditions associated with brain edema, including brain tumors, cerebral hemorrhage, brain trauma, and multiple sclerosis.^{36 37 38}

The activation of microglia, which could be recognized by their truncated processes and HLA-DR immunoreactivity, occurred in the rarefied WM at various intensities similar to those observed in WM lesions of heterogeneous causes.²⁷ These microglia tended to accumulate in the perivascular space and frequently accompanied APP-immunoreactive fibers. Therefore, the activated microglia may be a response to axonal damage, although it is also possible that the microglia were activated directly by chronic ischemia.

Oligodendroglia, which are the myelin-forming cells of the brain, decreased in number in regions in which myelin was severely degraded. It is generally believed that the number of oligodendroglia decreases in the brains of patients with Binswanger's disease.^{33 39 40} Similarly in the rat brain chronic cerebral hypoperfusion elicits a delayed decrease in the number of oligodendroglia in the WM.⁴¹ It remains unclear whether this loss of the oligodendroglia is caused by primary cellular damage or whether it is a dying-back phenomenon from the myelin injuries.

Degradation was not limited to the myelin components; it also involved axon cylinders in Binswanger's disease, as indicated by the accumulation of APP, synaptophysin, and CgA in the axons. It is likely that axonal damage is an early event in the process leading to the WM lesions, since labeling by these proteins also occurs in mild WM lesions.^{23 24} These proteins seem to accumulate because of compromised axonal transport, which may be secondary to the demyelinating process or, alternatively, to chronic hypoperfusion.

Consequently, the results of the present investigation indicate that Binswanger's diseased brains are characterized by regressive changes in the astroglia, the activation of microglia, and a decrease in the number of oligodendroglia, which are associated with the degradation of myelin component as well as an impairment in axonal transport. Of these pathological features, the activation of the microglia may have particular significance from the standpoint of treatment, since they may exert deleterious effects on the axons; this has been demonstrated by the coculture of neurons.⁴² In vivo studies involving the bilateral occlusion of the carotid arteries typically resulted in microglial activation and WM lesions.⁴³ The suppression of these lesions by cyclosporin A treatment supports the deleterious effects of the inflammatory glia on the WM.⁴⁴ Therefore, further research on the role of inflammatory cells in chronic ischemia may yield a clue to ameliorate the pathological changes that occur in the glia and axons in Binswanger's disease.

It remains unknown whether lacunar dementia⁴⁵ and Binswanger's disease are distinct entities or whether they are a spectrum of a single disease.^{45 46 47} The pathological findings of the glia and axons in Binswanger's disease were more diffuse and prominent but were not totally distinct from those seen in WM lesions of heterogeneous causes. However, these two disease conditions have different clinical features, and in the extreme Binswanger's disease is accompanied by unique pathological features such as diffuse WM lesions and perivascular collagen packing in the penetrating medullary arteries.^{48 49} The relationship between these two diseases should be more clearly defined in the future.

	Selected Abbreviations and Acronyms

 

APP = amyloid protein precursor CgA = chromogranin A GFAP = glial fibrillary acidic protein HLA-DR = human leukocyte antigen DR LCA = leukocyte common antigen PB = phosphate buffer WM = white matter

	Acknowledgments

 
We are indebted to Drs T. Kimura (Otowa General Hospital), H. Sugiyama (Kyoto-Minami National Hospital), and M. Kanda (Ijinkai Takeda General Hospital) for providing the autopsied brains, Drs Tokushima and Kitaguchi of Asahi Chemical Industry Co Ltd for providing APP592 and H. Flicker, M. Fukuda, and Y. Kitasaka for their excellent technical assistance. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Japanese Ministry of Education, Science, and Culture and one for amyotrophic lateral sclerosis.

Received January 21, 1997; revision received April 21, 1997; accepted April 29, 1997.

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