Cerebral amyloid angiopathy with granulomatous angiitis ameliorated by steroid-cytoxan treatment.

We report a case of a 62-year-old black woman who, 8 months prior to death, developed confusion, apraxias, disorientation, and difficulties with her vision. There was no dementia. Computed tomography (CT) scan and magnetic resonance imaging (MRI) suggested a tumor in the right posterior parietal white matter. A biopsy of the lesion displayed granulomatous angiitis and severe cerebrovascular amyloidosis, but no tumor was identified. Chronic inflammation with an occasional multinucleated giant cell was seen about the amyloid-infiltrated vessels. The cortex demonstrated gliosis but no plaques or tangles. Subsequently, the patient was treated with steroids and Cytoxan, with an improvement in her neurologic status. She died of opportunistic bronchopneumonia 8 months after the initial onset of her symptoms. On postmortem examination, the biopsied area of the brain showed atrophy with gliosis. Amyloid angiopathy was present but in much lesser degree than in the biopsy. Scant perivascular inflammatory infiltrates were seen only focally, and no giant cells were observed. The amyloid, both in the biopsy and autopsy material, was of the Alzheimer A4 type. This case suggests that steroid and cytoxan treatment ameliorated the angiitis and the amyloid angiopathy as well. The pertinent literature is discussed.

Cerebral arteriovenous malformations. A detailed morphological and immunohistochemical study using actin.

Vascular musculature was studied in cerebral arteriovenous malformations using a monoclonal antibody against the muscle protein actin in 20 cases. The more typical vessels (arterial and venous types) and a number of abnormalities of the muscular layer were identified. The latter included (1) partially developed media; (2) two layers of the media separated by a well-formed internal elastic membrane; (3) total or partial disarray of the muscle coat; and (4) partial absence of the media. Previously described large capillaries proved to be postcapillary venules by virtue of having a distinct muscular layer. Serial sectioning indicated that the previously described "polypoid projections" of the media are mostly artifacts and the concept of "arterialization of veins in arteriovenous malformations" could not be substantiated. The actin method proved to be a useful adjunct to the conventional stains for accurate and selective detection of smooth-muscle cells.

Astrocytes and the plaques of Alzheimer's disease.

We demonstrated senile plaques with glial fibrillary acidic protein (GFAP) stain in prefrontal and parietal cortex and in hippocampus of 3 cases of Alzheimer's disease. A plaque seen with GFAP appeared as a nearly round, spot-like brown blush consisting of numerous fine astrocytic processes, usually surrounded by single or, more often, several astrocytic cell bodies and their thick processes. Some plaques were virtually wrapped by these processes which also penetrated to the core, often directly touching the amyloid deposit. We never saw the plaque-type astrocytic grouping and spot-like blushes in the cortex of younger nondemented controls who were plaque negative. Our observations stress the importance of the astrocyte in plaque formation, either as primary or early secondary reactions. The focal glial reaction, without the neuritic component, possibly may precede neuritic change and relate to subminimal amyloid deposits or to some other undefined change.

The distribution of Alzheimer's neurofibrillary tangles and gliosis in chronic subacute sclerosing panencephalitis.

In two cases of clinically verified chronic subacute sclerosing panencephalitis (case 1, male, 15 years with a 9-year history; case 2, male, 20 years with a 9-year history) numerous Alzheimer's tangles (AT) were identified throughout the cerebral cortex (containing paired helical filament on electron microscopical examination). The brains were severely atrophic with hydrocephalus ex vacuo, occasional scattered microglial nodules, scant perivascular inflammatory infiltrates and demyelination. Only in case 1 were a few atypical intranuclear inclusion bodies noted. In the six-layered neocortex, a distinct distribution pattern of AT was observed; these lesions were mainly seen in laminae II, III and V (laminar distribution). The glial fibrillary acidic protein stain displayed extensive laminar gliosis mainly of the layers I, IIa, IV and VI; layers III and V, largely occupied by the AT, remained conspicuously spared from gliosis (especially the lamina III). Gliosis was prevalent in the white matter which was atrophic and shrunk. In the hippocampus, the AT involved many pyramidal neurons and, in this layer gliosis was lighter than in the surrounding white matter. In case 2, AT were present in the nucleus of Meynert, hypothalamus and in raphe centralis of the upper brain stem. Overall, the distribution of AT resembled that seen in Alzheimer's disease and aging; however, the senile plaques, vascular amyloidosis and granulovacuolar change were totally absent in both cases.

The widespread alteration of neurites in Alzheimer's disease may be unrelated to amyloid deposition.

The structural changes of Alzheimer's disease (AD) include a widespread alteration of neuronal cell processes in addition to senile plaques and neurofibrillary tangles. Since the antigenic characteristics of these abnormal neurites are similar to those of the abnormal neurites associated with the senile plaques, the question has been raised as to whether the widespread neuritic alteration is secondary to the deposition of amyloid. To answer this question, we examined brains from 2 subjects with a longer-lasting form of subacute sclerosing panencephalitis (SSPE) characterized by the presence of numerous neurofibrillary tangles but no senile plaques, 3 subjects with AD, and 2 age-matched controls. Light and electron immunocytochemical analyses revealed that abnormal neurites are present diffusely in SSPE cerebral cortex in the absence of amyloid deposits. These abnormal neurites were qualitatively identical to the widespread abnormal neurites of AD. The abnormal neurites, in contrast to the neurites of control brains, immunoreacted with antibodies to tau and ubiquitin. These distinctive antigenic features were due to the presence in these abnormal neurites of straight filaments, 14 to 16 nm in diameter, mixed with a few paired helical filaments. The spatial distribution of the widespread neuritic alteration correlated with that of neurofibrillary tangles in both conditions, but not with that of senile plaques in AD. The present findings demonstrate that a diffuse alteration of neurites similar to that present in AD takes place independently of the deposition of amyloid in SSPE, and they are consistent with the hypothesis that in AD, also, this alteration is not secondary to the deposition of amyloid.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute effect of the Nd:YAG laser on the cerebral arteriovenous malformation: a histological study.

The acute effect of Nd:YAG laser beam on cerebral arteriovenous malformations (AVMs) was examined. Histological examination of the specimens after treatment with the Nd:YAG laser revealed that the most prominent effect of the laser was shrinkage of the collagen of the vessels of the AVM, which led to laser-induced narrowing of blood vessels. The brain tissue confined to the resected AVM did not contain any histological evidence of acute damage. The resection of 10 cases of AVMs was safely accomplished with no morbidity or increased neurological deficits attributable to the laser technique.

Effect of insulin on acute experimental cerebral ischemia in gerbils.

We studied the effects of insulin with and without food deprivation on experimental cerebral ischemia in 197 gerbils. Ischemia was induced by unilateral common carotid artery occlusion for 4 hours. Gerbils were divided into four experimental groups and were studied for up to 1 week of survival: Group A (n = 50) was fed but received no insulin, Group B (n = 50) was deprived of food for 24 hours before surgery but received no insulin, Group C (n = 49) was fed and received daily injections of 0.1 IU lente insulin for 3 days before surgery, and Group D (n = 48) was deprived of food and received daily insulin injections. Insulin treatment was continued in Groups C and D after surgery. Blood glucose levels of all gerbils were determined before treatment (overall mean +/- SEM 88.0 +/- 12.4 mg/dl) and before carotid artery occlusion (Group A 92.2 +/- 18.3 mg/dl, Group B 81.4 +/- 11.7 mg/dl [p less than 0.05 different from before treatment], Group C 92.8 +/- 22.3 mg/dl, and Group D 66.1 +/- 24.0 mg/dl [p less than 0.001 different from before treatment]). Among the four groups, 52 gerbils died within 1 week. Neurologic deficits were scored and histologic evidence of the infarcts was graded in survivors at 1 week. Group C gerbils had the best stroke index scores. Histologic evaluation revealed that 35.9% of Group A, 21.1% of Group B, 13.9% of Group C (p less than 0.05 compared with Group A), and 28.1% of Group D survivors developed cerebral infarcts.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral aging: a quantitative study of gliosis in old nude mice.

Morphometric glial fibrillary acidic protein (GFAP) studies of the brains of 11 old (18-29 months) female, outbred athymic mice demonstrated astrocytic gliosis (increase in GFAP-positive astrocytes; GFAP-PA) in all mice with a consistent distribution pattern. Specific areas such as the central white matter, hippocampus, diencephalon, gray matter at the floor of the 4th ventricle, and posterior colliculi showed the change most conspicuously, revealing GFAP-PA both interstitially and perivascularly. There was no apparent demyelination in the affected white matter. In addition, there was an increase in GFAP-PA in the external limiting membrane surrounding the diencephalon and base of brain stem, but only to a minor degree over the cerebral hemispheres. The cerebral and cerebellar cortices and hypothalamus showed no significant increase. In contrast, all of the 2-month-old control animals showed only minor amounts of GFAP-PA, seen in the external limiting membrane and a trace in the cerebral white matter. The present data suggest that astroglial sclerotic change in various regions of the brain is an important morphological expression of cerebral aging. In view of the lack of other demonstrable histological changes (i.e., silver and amyloid stains were negative) or significant atrophy, the cause of the observed gliosis in BALB/c mice might represent a genuine aging change. As an incidental finding, aggregates of PAS-positive granules were noted in the Ammon's horn of most old animals, while none were seen in the young controls.

Cerebral amyloid angiopathy and astrocytic gliosis in Alzheimer's disease.

Astrocytic reaction at amyloid infiltrated cortical vessels was studied using glial fibrillary acidic protein (GFAP) stain in two cases of Alzheimer's disease (AD). Sections from the visual and prefrontal cortex were stained with H&E, Bodian, Congo red, and thioflavin S in addition to GFAP. Senile plaques and neurofibrillary tangles were present in both cases. The density of astrocytes surrounding vessels infiltrated with amyloid was variable. In the same area, there were vessels with minimal perivascular astrocytic reaction as well as vessels displaying more pronounced perivascular gliosis; there was no constant excessive gliosis around vessels with severe amyloid deposits. However, if amyloid infiltrating the vessel wall protruded into the perivascular neuropil of the cortex, then prolific reaction of astroglia, similar to that seen at interstitial senile plaques was apparent, and a neuritic component was distinct. It appears that once amyloid of AD type is deposited in the neuropil, whether in form of interstitial plaque or perivascular plaque, it causes a similar astroglial and neuritic reaction.

Oligodendroglial proliferative abnormality associated with arteriovenous malformation: report of three cases with review of the literature.

A peculiar nonneoplastic oligodendroglial proliferative abnormality associated with cerebral arteriovenous malformations (AVMs) was present in three patients. Histological examination of biopsy material revealed dense oligodendroglial tissue reminiscent of oligodendroglioma in the white matter adjoining the AVMs. Careful consideration of clinical and pathological features suggested that the evidence was insufficient to qualify the lesion as truly neoplastic (oligodendroglioma); rather, a tissue collapse or a hamartomatous proliferation could be considered to be its cause. The literature contains 14 instances of various vascular malformations associated with primary brain tumors, 5 of which were diagnosed as oligodendrogliomas. It is possible, however, that some of the cases reported in the literature constitute oligodendroglial abnormality similar to that observed in our cases rather than genuine oligodendrogliomas. Attention is drawn to this interesting and prognostically important phenomenon.

Hyalinizing plasmacytic granulomatosis of the falx.

Computed tomography scan in a 43-year-old woman revealed a fusiform mass involving the falx. Pathological tissue removed at craniotomy revealed a hyalinizing plasmacytic granulomatosis composed of masses of lymphocytes, plasmacytes, and various sized islands of hyalinized fibers arranged in parallel and surrounded by multinucleated giant cells. Ultrastructurally, the hyalinized fibers consisted of electron-dense, amorphous deposits. After partial removal, irradiation, and steroid therapy, the lesion decreased considerably in size.

Alzheimer's tangles in sudanophilic leukodystrophy.

We present a case of infantile leukodystrophy with some sudanophilic features. A normally developed male infant did well until age 15 months. Then he had episodes of myoclonus, reversal of intellectual development, rigidity with decerebrate posturing and epilepsy, which became severe. He died at age 7 years, 10 months. On autopsy, the brain was normally developed, but there was severe demyelination and gliosis throughout the white matter; the cerebellar cortex showed atrophy. The striking, unexpected finding was the presence of numerous Alzheimer's tangles containing paired helical filaments in electronmicroscopic examination, not only in the cerebral cortex but also in the brainstem, basal ganglia, and hypothalamus including the nucleus basalis of Meynert. Other unusual findings were hyperostosis of the skull and the appearance of macrophages containing PAS-positive granules in the reticuloendothelial system in many organs.

Atypical Gerstmann-Straüssler syndrome or familial spinocerebellar ataxia and Alzheimer's disease?

We report a neuropathologic study of a case with features of Gerstmann-Straüssler syndrome (GSS) that is remarkable for the large number of neurofibrillary tangles (NFTs) throughout the neuraxis. The patient had a family history of spinocerebellar ataxia, but without dementia in other affected members. Our case meets the cardinal features of GSS as a rare familial degenerative disease characterized by clinically, spinocerebellar ataxia accompanied by progressive dementia, and pathologically, multiple system atrophy combined with widespread amyloid plaque deposition in the cerebral and cerebellar cortex. However, most pathologic studies stress the absence of NFTs in GSS. The nosology of this case is difficult to resolve because of profuse NFTs and morphologic differences between our and comparison Alzheimer's disease (AD) cases, the most prominent being spongiform changes. This case is remarkable because it combines features of a number of CNS degenerative diseases, including multiple system atrophy, AD, spongiform encephalopathies, and cerebrovascular amyloidosis.

Lectin histochemistry of plaques and tangles in Alzheimer's disease.

Biotinyl derivatives of several lectins and avidin-horseradish peroxidase were used to study the localization of glycoconjugates in amyloid plaques and in neuritic tangles in brains of patients with Alzheimer's disease (AD), Downs syndrome (DS) and Gerstmann-Sträussler syndrome (GSS). The lectins tested recognize the following residues: beta-D-galactosyl [Ricinus communis agglutinin 120, (RCA-1) and peanut agglutinin, (PNA)]; alpha-D-galactosyl [Griffonia simplicifolia agglutinin (GSA)]; alpha-D-mannosyl greater than alpha-D-glucosyl [concanavalin A (Con A) and Lens culinaris agglutinin (LcH)]; N-acetyl- and N-glycolyl-neuraminic acid [Limax flavus agglutinin (LFA) and Limulus polyphemus agglutinin (LPA)]; N-acetyl-glucosaminyl and sialyl [wheat germ agglutinin (WGA)]; N-acetyl-D-galactosaminyl [Helix pomatia agglutinin (HPA) and Dolichos biflorus agglutinin (DBA)] and alpha-L-fucosyl [Ulex europeus agglutinin (UEA-1)]. The majority of lectins listed above bind preferentially to the peripheral area of AD plaques, whereas in plaques of DS they are mainly bound to central amyloid core. In neurofibrillary tangles of AD brains only residues recognized by WGA and HPA or DBA were found, whereas in DS brains, in addition to above mentioned, beta-D-galactose (RCA-1) and sialic acid (LFA) were also present. In brain microblood vessels the strongest reaction in endothelia appeared with UEA-1 and RCA-1, indicating the abundance of alpha-L-fucosyl and beta-D-galactosyl residues. In AD brains deposits of amyloid were noted in the wall of some blood vessels, where monosaccharide residues recognized by RCA-1, GSA, UEA and WGA but not by Con A and LFA were present. However, our studies of some organs (liver, kidney, heart and testes) of patients with generalized amyloidosis revealed a lack of these sugar residues. It indicates, that the composition of amyloid present in brains of AD is different to that in other organs in generalized amyloidosis.

Case-control study of clinical outcome after aneurysmal subarachnoid hemorrhage.

The clinical and neuropathological features of 84 nonsurvivors of aneurysmal subarachnoid hemorrhage (consecutive autopsy series) were compared with those of 51 survivors (consecutive clinical series). The groups differed significantly in the type of bleeding: 58% of the nonsurvivors had massive subarachnoid hemorrhage (MSAH) compared to 10% of the survivors (P less than 0.00001); 54% of the nonsurvivors had intraventricular hemorrhage (IVH) compared to 29% of the survivors (P less than 0.008); 45% of the nonsurvivors had intracerebral hematoma (ICH) compared to 8% of the survivors (P less than 0.00001). Only 1 of the 19 patients with both MSAH and ICH survived. The incidence of cerebral infarction was similar in nonsurvivors (31%) and survivors (29%). In the absence of associated MSAH, IVH, or ICH, cerebral infarction was uncommon (11%). Documented in-hospital rebleeding was uncommon in nonsurvivors (13%) and survivors (2%). Admission neurological status did not predict outcome independent of the extent of the initial bleeding. Comparison of the two groups suggests that the type and extent of initial bleeding are the most important determinants of mortality in aneurysmal subarachnoid hemorrhage.

The morphology and biologic behavior of human glioblastoma growing in nude mice.

Seven human glioblastomas (five small cell glioblastomas [SCG] and two anaplastic astrocytomas with giant cells [AA]) grown in serial passage in BALB/c nude mice and nude rats, were studied histologically and compared to human donor tumors. Four SCG maintained many basic features seen in donor tissue, i.e., cell type, tendency to produce micronecrotic palisading (MNP), high cellularity, numerous mitoses. Significant vascular proliferation was seen only in nude rat hosts of one of the SCG lines transplanted from mice at passage 11. Giant capillaries, cyst formation and hemorrhages were features of large (1.0 cm) heterotransplanted SCG. One SCG altered morphology from first passage, showing an adenoid pattern and mucinous change. Both AA preserved original tissue characteristics in initial passages. Later dedifferentiation occurred with small cells predominating. These small cells were larger and rounder than those of the SCG. Large AA showed central necrosis but rarely MNP, hemorrhages and focal inflammatory infiltrates.

Cerebral amyloid angiopathy: the vascular pathology and complications.

Twenty-five cases with cerebral amyloid angiopathy (CAA) were studied. Senile plaques (SP) were present in all cases. In only eight cases which also displayed either SP (two cases), or both SP and Alzheimer's neurofibrillary tangles (NFT) (six cases), was there a history of dementia. In five cases, SP and NFT were observed without a history of dementia. Seven cases had significant cerebral hemorrhage, single or multiple, which could be related to CAA. Ten cases had cerebral infarcts, but only in seven of these cases could the infarcts be related to CAA. In five cases, with moderate to severe CAA and no history of dementia other distinctive vascular changes were also noted in the brain. These CAA-associated vasculopathies (CAA-AV) consisted of: clusters of multiple arteriolar lumina, the so-called "glomerular" formations, with various degrees of amyloid infiltration; aneurysmal vessels with amyloid infiltration; obliterative intimal changes; "double barreling", chronic inflammatory perivascular or transmural infiltrates; hyaline (nonamyloid) arteriolar degeneration, with or without aneurysmal dilatation; and fibrinoid necrotizing vascular change. In all five cases with CAA-AV, there were cerebral infarcts or hemorrhages which were considered to be direct complications of amyloid angiopathy, or of the vasculopathies developing secondary to the amyloid infiltration of vessel walls. It is possible that the associated vasculopathies represented secondary vascular changes that followed amyloid deposition in the blood vessel walls.

Experimental cerebral infarction in Mongolian gerbils: effects of vincamine on lesion size, survival and behavior.

Vincamine was administered to gerbils at doses of 0, 1, 2, 10 and 40 mg/kg/d to study its effect on survival, extent of ischemic brain lesion, locomotor activity, neurologic signs, stool production, and food and water intake after unilateral carotid occlusion. Drug and placebo were delivered by implantation of osmotic minipumps. The three most important criteria, increase in survival, reduction in cerebral lesion in survivors, and functional recovery of locomotor activity were all significantly improved by vincamine treatment at all doses. Since the lowest dose produced as much improvement as the higher doses it was concluded that increasing dose beyond 1 mg/kg/d was not beneficial using the measures reported here.

Neural, pituitary, and mammary tumors in Sprague-Dawley rats treated with X irradiation to the head and N-Ethyl-N-nitrosourea (ENU) during the early postnatal period: a statistical study of tumor incidence and survival.

To study the late effects of early postnatal treatment with N-ethyl-N-nitrosourea (ENU) preceded by X irradiation to the head, 226 neonatal CD rats were divided into six groups which received the following treatment: (1) 500-rad X irradiation to the head on the third postnatal day (pnd); (2) injection ip with 30 mg/kg ENU on the fourth pnd; (3) injection ip with 30 mg/kg ENU on the seventh pnd; (4) a combination of 500-rad X irradiation to the head on the third pnd, followed by ip 30 mg/kg ENU on the fourth pnd; (5) a combination of 500-rad X irradiation to the head on the third pnd, followed by ip 30 mg/kg ENU on the seventh pnd; and (6) untreated controls. The results indicate that (1) X irradiation to the head alone significantly extended the life span of females compared to that of control females, and did not affect survival of males; (2) X irradiation did not influence the latent period or mortality from neurogenic tumors when ENU was given 1 or 3 days afterward; (3) ENU itself was a factor in shortening latent periods for mammary tumors; (4) X irradiation alone did not increase the incidence of mammary tumors, and revealed no protective effect on the ENU-induced mammary carcinogenesis; (5) X irradiation increased the prevalence of pituitary tumors in the females; (6) no enhancement of pituitary tumors by ENU was observed: and (7) there was a statistically significant association of pituitary and mammary tumors in females.

The effect of treatment with Corynebacterium parvum on the development and growth of experimental hematogenic metastases of schwannoma in the rat.

Single i.v. administration of Corynebacterium parvum 5 days before i.v. injection of 10(6) tissue cultured syngeneic schwannoma cells in Lewis rats resulted in extension of survival time (P less than 0.05). There was a significant decrease in metastatic tumor incidence for lung, heart, and kidney and decreased lung tumor growth with approximately 50% of the lung tumor burden of untreated controls (P less than 0.05). Rats treated similarly with C. parvum 10 days after tumor cell injection showed no enhanced survival; to the contrary, their survival was shortened. Moreover, tumor incidence in the post-treated group was not significantly different from the control but significantly increased in comparison to the pretreated group. Enhanced lung tumor growth resulted in a final tumor burden about twice that of untreated controls (P less than 0.05).