A Unique Case of Post-Subarachnoid Hemorrhage Cerebral Atrophy and Its Implications on Alzheimer’s Disease

Abstract

Subarachnoid hemorrhage (SAH) has been reported to cause glial scarring within a short timeframe. Due to the high mortality rate of SAH, there is limited research on its long-term effects and relation to neurodegenerative disorders. This report aims to investigate a combination of healed SAH and Alzheimer’s Disease (AD) pathology. A 90-year-old female cadaver, in the anatomy laboratory, was found to have an irregular surgical scar in the right frontoparietal bone. Upon dissection, the right frontal lobe was discovered to be atrophic with a concavity. Histopathology exhibited significant gliosis and corpora amylacea (CA). The cause of death was AD, and past medical history revealed an aneurysmal SAH during childbirth 60 years ago. CA and gliosis are common findings in aging, ischemia, and AD. These findings contribute to the knowledge of the long-term effects of SAH and necessitate further research on the pathogenesis of AD in relation to cerebral ischemia.

Introduction

Subarachnoid hemorrhage (SAH) is catastrophic bleeding into the subarachnoid space due to a traumatic or nontraumatic cause. ¹ Of the nontraumatic cases, around 85% are aneurysmal subarachnoid hemorrhage (aSAH), exacerbated by factors such as hypertension, older age, and alcohol or drug use. ¹ Aneurysmal SAH has a mortality rate of 32-67%, often during the acute stage, due to irreversible brain damage that results from ischemic complications. ² Acute postmortem changes within 72 hours post-SAH showed cytotoxic edema, congestion, and multiple infarcts with neuronal death. ² Additionally, brain injury was found to trigger glial scar formation through the upregulation of markers such as glial fibrillary acidic protein. ³

Alzheimer’s disease (AD) is a common neurological disease characterized by deficits in memory and cognitive function due to neurofibrillary tangles and β-amyloid plaques that cause neuron loss and eventually cognitive decline. ⁴ Many aspects of the pathophysiology of AD are not fully understood, including its relationship to pathology associated with cerebrovascular disease. ⁴ Given the high mortality, short time window of treatment, and a more significant focus on acute changes, there is limited research on the long-term effects of SAH, especially in the setting of age-related neurodegenerative disorders such as AD.

This report highlights a unique finding of brain pathology due to a combination of long-term healed aSAH and AD in a cadaver. It investigates the association between these two pathologies in an individual who survived six decades after an ischemic event and emphasizes the process of integrating structural findings and medical history to inform clinical correlations.

Case Report

During a routine dissection in the anatomy laboratory, a 90-year-old female cadaver with a reported cause of death of AD was examined. The limited available medical history indicated that the donor experienced a massive brain aneurysm rupture of unknown location during childbirth in her thirties. Three surgeries were performed to repair the damage, leading to a prolonged but complete recovery over the following 11 months. The donor lived for approximately sixty more years and eventually died of AD.

An irregular and hypertrophic scar was discovered on the right frontoparietal bone (Figure 1A). Upon further dissection, a large concavity was found in the right frontal lobe (Figure 1B). The brain was carefully removed, and the following structures were examined: the cerebral hemispheres, ventricles, and intracranial and extracranial neurovasculature, including the external/internal jugular veins, external/internal carotid arteries, and the arteries contained in the Circle of Willis. Multiple photographs were taken, and the dimensions of the relevant structures were measured using digital calipers. Tissue samples of the frontal lobes were obtained bilaterally from the subpial regions for histopathological examination, stained with hematoxylin and eosin, and observed under microscopy.

Figure 1.

(A) Right side of the skull showing surgical scar (B) Right frontal lobe showing atrophy (C) Right and left hemisphere sections showing that the right hemisphere is smaller than the left

The concave defect in the right frontal lobe was irregular and measured 4 × 3 × 2.5 cm (Figure 1B). The right cerebral hemisphere was considerably smaller than the left hemisphere (Figure 1C). The right hemisphere length was 1.5 cm shorter than the left hemisphere; conversely, the width was slightly greater by 0.5 cm on the right (Table 1). No abnormalities or evidence of surgical clippings were found in the vasculature or other surrounding structures during the intracranial and extracranial examination. The histopathology report of the brain sections exhibited significant gliosis and corpora amylacea bilaterally (Figure 2). The corpora amylacea appeared as darkly stained spherical or ovoid structures with concentric rings. The glial scarring, with increased density compared to the surrounding tissue, involved reactive astrocytes. The report indicated that the findings were suggestive of healed cerebral infarcts but were also consistent with AD and vascular dementia (VaD).

Table 1.

Dimensions of the Right and Left Cerebral Hemispheres

	Length (cm)	Height (cm)	Width (cm)
Right hemisphere	15 cm	9 cm	5.5 cm
Left hemisphere	16.5 cm	9 cm	5 cm

Figure 2.

Histopathological examination of the cerebrum showing CA (black arrows) and astrocytes (blue arrows)

Discussion

Given the donor’s long-term survival following SAH and subsequent death roughly 60 years later due to AD, it remains uncertain if these two pathologies are related. Research surrounding the long-term survival of SAH is limited, often only assessing the acute stages (up to 72 hours post-ischemic event). ² However, one study reported that patients who survived SAH experienced a higher long-term risk and earlier onset of dementia compared to both the control group and ischemic survivors. ⁴ In this case, the unilateral concave defect of the right cerebrum, likely from the massive aSAH, along with overall atrophy of the right side compared to the left, does not align with the classic findings of AD. Typically, AD presents with bilateral and variable cortical atrophy, mainly affecting the frontal, temporal, and parietal lobes, characterized by gyral narrowing, sulcal widening, and an overall reduction in brain volume. ⁵ Therefore, in this case, there may be a potential connection between AD and healed SAH.

Clinical History and Diagnosis

The (cadaveric) donor, who was hospitalized for childbirth in the 1960s, experienced a rupture of an aneurysm during her hospital stay. The risk of developing an aneurysm and its rupture resulting in SAH is higher in the later stages of pregnancy and 6 weeks postpartum, which is attributed to factors such as loss of elasticity, smooth muscle hyperplasia, and cardiovascular changes due to vascular physiological changes. ⁶ After aneurysmal rupture, the donor underwent three surgical interventions to address the SAH. The irregular and hypertrophic scar was likely due to open craniotomy with obliterative clipping, which was the preferred treatment at the time. ⁷ Surgical treatment of aSAH has evolved over the past several decades. Currently, endovascular coiling is the preferred treatment for aneurysms, while surgical clipping is reserved for specific reasons, including tortuosity of the bleeding vessels. ⁸ Rebleeding was reported in 4% to 15% of patients within the first 24 hours of aSAH, and the risk declined over the following 2 weeks, with rebleeding often requiring secondary surgical intervention. ⁸ It was likely that the donor experienced rebleeding, which led to her needing repeated surgeries.

Alzheimer’s disease was listed as the cause of death; however, the clinical records were not available, and the basis for the diagnosis could not be verified. There are several different types of dementia, the 2 most common being AD and VaD, which can commonly co-occur. ⁹ AD is typically characterized by short-term memory loss that progresses over months to years. ⁹ Pathology of AD typically reveals diffuse brain atrophy with β-amyloid plaques and phosphorylated tau tangles on histology. ⁹ Comparatively, VaD presents with acute dementia and focal neurological deficits in a stepwise correlation with vascular events. ⁹ Pathology often demonstrates diffuse, small infarcts or local, large infarcts and is correlated with cerebral vessel pathology. ⁹ In this case, establishing a definitive diagnosis is challenging. The donor experienced a significant vascular insult due to subarachnoid hemorrhage, but it is unknown whether additional cerebrovascular disease was present. Reports indicated that she had fully recovered from the event. The differentiation of AD and VaD is therefore difficult, and the pathology likely represents a co-occurring presentation.

Corpora Amylacea

Corpora amylacea (CA), also referred to as “wasteosomes”, are spherical, translucent structures produced by astrocytes, averaging about 15 μm in diameter, characterized by multiple concentric short linear densities with a narrow rim of fibrils in the periphery.^10,11 They are commonly found in aging brains but can be seen extensively in conditions such as AD, multiple sclerosis, and epilepsy. ⁹ While largely discussed in neurologic conditions, CA have also been found broadly in the body including the prostate, respiratory system, and numerous tumors with a general function of waste accumulation. ¹¹ The CA are believed to serve a protective role by collecting cellular waste products and are often associated with oxidative stress, ageing, and many pathological conditions.^10,11 CA vary in content, with some containing fibrillary amyloid proteins and both intracellular and extracellular components, but all CA have glycan structures in common. ¹¹ In AD, CA contain proteins such as ubiquitin and tau. ¹⁰ Additionally, in both VaD and AD, CA is found diffusely in perivascular, periventricular, and subpial regions. ¹⁰ The presence of extensive, diffuse CA in this case was most likely secondary to both chronic ischemia and AD.

Gliosis

Ischemic injury can lead to reactive gliosis, which upregulates the expression of brain markers, eventually causing glial scarring. ³ In the acute phase, glial scars have several beneficial properties, including tissue remodeling, prevention of cellular damage and inflammatory spread, and supporting nervous tissues. ³ However, in the long term, glial scars hinder axon regeneration due to the secretion of inhibitory molecules by astrocytes. ³ Many neurodegenerative diseases, including AD, induce reactive astrocytes similar to ischemia. ¹² The affected tissue is replaced with extracellular matrix components via activated astrocytes, which secondarily involve microglia to form glial scars. ¹² In AD, astrogliosis is particularly prominent around amyloid plaques, which contain accumulations of β-amyloid, since the activated astrocytes aid plaque generation and subsequently induce an inflammatory neuronal injury.^6,13 Both ischemia and AD provide an inflammatory environment that potentiates glial scar formation and contributes to further damage.

Conclusion

In conclusion, the findings of this 90-year-old donor highlight the complex interplay between chronic ischemic changes resulting from SAH and the progression of AD. This work emphasizes the importance of integrating gross structural findings, medical history, and histopathology to develop a comprehensive understanding of AD. The extensive CA and prominent gliosis in the cerebrum overlapped with AD pathology and likely provoked disease progression. The findings contribute significantly to the growing body of literature on the mechanisms underlying AD in individuals with a history of SAH, emphasizing the need for targeted research to better understand the pathogenesis of AD in survivors of SAH.