Cerebral Amyloid Angiopathy Cases Research Articles

Distinct neuroinflammatory patterns between cerebral microbleeds and microinfarcts in cerebral amyloid angiopathy.

In this neuropathological study, we investigated neuroinflammation surrounding recent and old cerebral microbleeds (CMBs) and cerebral microinfarcts (CMIs) in 18 cases of cerebral amyloid angiopathy (CAA). We used several serial stainings and immunolabellings to identify microvascular lesions, define their recent or old stage, and characterize neuroinflammatory response (scavenging activity and astrogliosis). We found that both CMBs and CMIs induce a neuroinflammatory response, which was more pronounced in old lesion than recent. Astrogliosis and scavenging activity were differentially prominent according to the ischemic/hemorrhagic nature of the lesion. Our findings provide insights into the pathophysiology of microvascular injuries in CAA.

Prion diseases, always a threat?

Prion diseases are caused by prions, which are proteinaceous infectious particles that have been identified as causative factors of transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD). Prion diseases are devastating neurodegenerative disorders in humans and many animals, including sheep, cows, deer, cats, and camels. Prion diseases are classified into sporadic and genetic forms. Additionally, a third, environmentally acquired category exists. This type includes kuru, iatrogenic CJD caused by human dura mater grafts or human pituitary-derived hormones, and variant CJD transmitted through food contaminated with bovine spongiform encephalopathy prions. Bovine spongiform encephalopathy and variant CJD have nearly been controlled, but chronic wasting disease, a prion disease affecting deer, is spreading widely in North America and South Korea and recently in Northern Europe. Recently, amyloid-beta, alpha-synuclein, and other proteins related to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases were reported to have prion features such as transmission to animals. Amyloid-beta transmission to humans has been suggested in iatrogenic CJD cases and in cerebral amyloid angiopathy cases with cerebral bleeding occurring long after childhood neurosurgery with or without cadaveric dura mater transplantation. These findings indicate that diseases caused by various prions, namely various transmissible proteins, appear to be a threat, particularly in the current longevity society. Prion disease represented by CJD has obvious transmissibility and is considered to be an “archetype of various neurodegenerative diseases”. Overcoming prion diseases is a top priority currently in our society, and this strategy will certainly contribute to elucidating pathomechanism of other neurodegenerative diseases and developing new therapies for them.

Iatrogenic cerebral amyloid angiopathy in older adults.

An increasing number of cases of iatrogenic cerebral amyloid angiopathy (CAA) have now been reported worldwide. Proposed diagnostic criteria require a history of medical intervention with potential for amyloid-β transmission, for example those using cadaveric dura mater or requiring instrumentation of the brain or spinal cord. Clinical presentation occurs after an appropriate latency (usually three or four decades); to date, most patients with iatrogenic CAA have had 'early-onset' disease (compared to sporadic, age-related, CAA), as a consequence of childhood procedures. We describe five cases of possible iatrogenic CAA in adults presenting in later life (aged 65 years and older); all had prior neurosurgical interventions and presented after a latency suggestive of iatrogenic disease (range 30-39 years). Use of cadaveric dura mater was confirmed in one case, and highly likely in the remainder. The presentation of iatrogenic CAA in older adults widens the known potential spectrum of this disease and highlights the difficulties of making the diagnosis in this age group, and particularly in differentiating iatrogenic from sporadic CAA. Increased vigilance for cases presenting at an older age is essential for furthering our understanding of the clinical phenotype and broader implications of iatrogenic CAA.

Tissue inhibitor of matrix metalloproteinases 4: a novel marker associated with CAA

AbstractBackgroundWe have previously shown that matrix metalloproteinase 9 (MMP9) and tissue inhibitor of proteinases 3 (TIMP3) are specifically expressed in the vasculature of patients with cerebral amyloid angiopathy (CAA). Moreover, we have demonstrated increased MMP9 and decreased TIMP3 levels, as well as an altered MMP9:TIMP3 ratio in the vasculature of CAA patients that suffered from intracerebral haemorrhages (CAA‐ICH) compared to CAA patients without ICH (CAA‐nonICH). We now extended our studies to investigate whether TIMP4 may have a similar role in CAA, as this has not been studied before.MethodUsing immunohistochemistry, we studied occipital lobe tissue of 44 controls (mean age 78.4 years; 50% female) and 58 CAA patients (77.5 years; 55% female; 40 CAA‐nonICH and 18 CAA‐ICH). Vascular TIMP4 staining was scored in a semiquantitative manner. Using ELISA, we measured TIMP4 CSF levels of 33 CAA patients (mean age 72.2 years; 47% female) and 35 controls (mean age 71.2 years; 51% female). For a subset of CSF samples (11 CAA samples and 14 controls), the levels of MMP2, MMP9, and MMP14 have been determined previously, and now their ratios to TIMP4 were calculated. Differences between CAA patients and controls were assessed using (ordinal) linear regression analysis.ResultIn brain tissue, CAA cases had increased vascular TIMP4 expression when compared to controls (p = 0.00002, figure 1). TIMP4 expression did not differ between CAA‐nonICH and CAA‐ICH cases. In the absence of vascular TIMP4 staining, we often observed perivascular staining. Decreased levels of perivascular TIMP4 staining were observed in CAA‐ICH cases when compared to CAA‐nonICH cases (p = 0.045) and to controls (p = 0.035). CSF levels of TIMP4 were decreased in CAA patients compared to controls (p = 0.03, figure 2). In addition, the ratios of MMP2 (p = 0.038), MMP9 (p = 0.005), and MMP14 (p = 0.025) to TIMP4 were increased in CAA patients compared to controls.ConclusionWe demonstrated increased TIMP4 expression in vessel walls of CAA patients compared to controls. In contrast, TIMP4 CSF levels were decreased in CAA patients compared to controls, whereas MMP:TIMP4 ratios were increased, indicating a disbalance of MMP/TIMP4 levels in CAA pathophysiology.Funding: BIONIC project (no. 733050822, ZonMW) and CAFÉ project (no. 5R01NS104147‐02, NIH).

Subcortical hemorrhage caused by cerebral amyloid angiopathy compared with hypertensive hemorrhage

ObjectivesMost published reports on lobular hemorrhage in cerebral amyloid angiopathy (CAA) include patients diagnosed only by imaging studies. This study analyzed patients with subcortical hemorrhage histologically diagnosed as CAA or non-CAA (hypertensive). MethodsThis is a retrospective study analyzing data from 100 craniotomy cases. Tissue of hematoma cavity wall was collected for histological investigation in hematoma removal by surgery in patients with subcortical hemorrhage. Statistical analyses of blood pressure, hematoma location and volume, outcome, and mortality was performed in CAA and non-CAA groups. ResultsThere were 47 CAA and 53 non-CAA cases, and average age was significantly older in the CAA group (p < 0.01). Blood pressure was significantly lower (p < 0.01) but hematoma volume was significantly greater (p < 0.05) in the CAA group. Rebleeding occurred in two CAA cases and one non-CAA case, but no re-operations were required. Average score of modified Rankin Scale, which is used to measure the degree of disability in patients who have had a stroke, at three months after surgery was not significantly different between the two groups (CAA: 3.94 ± 1.28, non-CAA: 3.58 ± 1.50). There were seven deaths in the CAA and six in the non-CAA group, and intraventricular hemorrhage highly complicated in the death cases in both groups. In the CAA group, average age of the fatal cases was significantly older than that of the surviving cases (p < 0.05) and six cases demonstrated dementia before onset of hemorrhage. ConclusionsSurgical removal of a subcortical hemorrhage caused by CAA is not contraindicated. However, age > 80 years, complication with intraventricular hemorrhage, hematoma volume ≥ 50 ml, and dementia before onset of hemorrhage contribute to high mortality, and craniotomy should be carefully considered for such patients. A limitation of this study is that comparison between CAA and non-CAA groups was performed in the patients with only surgically indicated ICH, and does not evaluate entire ICH cases with CAA. However, this study appropriately compared pathologically diagnosed CAA and non-CAA in patients with moderate to severe lobular ICH with surgical indications.

Histopathological Correlates of Lobar Microbleeds in False-Positive Cerebral Amyloid Angiopathy Cases.

A definite diagnosis of cerebral amyloid angiopathy (CAA), characterized by the accumulation of amyloid β in walls of cerebral small vessels, can only be obtained through pathological examination. A diagnosis of probable CAA during life relies on the presence of hemorrhagic markers, including lobar cerebral microbleeds (CMBs). The aim of this project was to study the histopathological correlates of lobar CMBs in false-positive CAA cases. In 3 patients who met criteria for probable CAA during life, but showed no CAA upon neuropathological examination, lobar CMBs were counted on ex vivo 3T magnetic resonance imaging (MRI) and on ex vivo 7T MRI. Areas with lobar CMBs were next sampled and cut into serial sections, on which the CMBs were then identified. Collectively, there were 25 lobar CMBs on in vivo MRI and 22 on ex vivo 3T MRI of the analyzed hemispheres. On ex vivo MRI, we targeted 12 CMBs for sampling, and definite histopathological correlates were retrieved for 9 of them, of which 7 were true CMBs. No CAA was found on any of the serial sections. The "culprit vessels" associated with the true CMBs instead showed moderate to severe arteriolosclerosis. Furthermore, CMBs in false-positive CAA cases tended to be located more often in the juxtacortical or subcortical white matter than in the cortical ribbon. These findings suggest that arteriolosclerosis can generate lobar CMBs and that more detailed investigations into the exact localization of CMBs with respect to the cortical ribbon could potentially aid the diagnosis of CAA during life. ANN NEUROL 2023;94:856-870.

Cortical superficial siderosis is associated with reactive astrogliosis in cerebral amyloid angiopathy

BackgroundCortical superficial siderosis (cSS) has recently emerged as one of the most important predictors of symptomatic intracerebral hemorrhage and is a risk factor for post-stroke dementia in cerebral amyloid angiopathy (CAA). However, it remains unknown whether cSS is just a marker of severe CAA pathology or may itself contribute to intracerebral hemorrhage risk and cognitive decline. cSS is a chronic manifestation of convexal subarachnoid hemorrhage and is neuropathologically characterized by iron deposits in the superficial cortical layers. We hypothesized that these iron deposits lead to local neuroinflammation, a potentially contributory pathway towards secondary tissue injury.MethodsAccordingly, we assessed the distribution of inflammatory markers in relation to cortical iron deposits in post-mortem tissue from CAA cases. Serial sections from the frontal, parietal, temporal, and occipital lobes of nineteen autopsy cases with CAA were stained with Perls’ Prussian blue (iron) and underwent immunohistochemistry against glial fibrillary acidic protein (GFAP, reactive astrocytes) and cluster of differentiation 68 (CD68, activated microglia/macrophages). Digitized sections were uploaded to the cloud-based Aiforia® platform, where deep-learning algorithms were utilized to detect tissue, iron deposits, and GFAP-positive and CD68-positive cells.ResultsWe observed a strong local relationship between cortical iron deposits and reactive astrocytes. Like cSS-related iron, reactive astrocytes were mainly found in the most superficial layers of the cortex. Although we observed iron within both astrocytes and activated microglia/macrophages on co-stains, there was no clear local relationship between the density of microglia/macrophages and the density of iron deposits.ConclusionIron deposition resulting from cSS is associated with local reactive astrogliosis.

Abstract 164: Cerebral Amyloid Angiopathy Is Associated With A Higher Risk Of Subdural Hemorrhage: Combined Analysis Of The Uk Biobank And All Of Us

Background: Cerebral amyloid angiopathy (CAA) is a condition characterized by amyloid deposition in the brain’s blood vessels. CAA is a common cause of spontaneous intracerebral hemorrhage (ICH) in older patients. Although other types of intracranial hemorrhages can occur in conjunction with CAA-related ICH, it is unknown whether CAA is a risk factor for other types of intracranial hemorrhage in the absence of ICH. Hypothesis: CAA is an independent risk factor for isolated non-traumatic subdural hemorrhage (SDH). Methods: We conducted a 2-stage (discovery and replication) observational study that retrospectively analyzed data from the UK Biobank (discovery phase) and the All of Us (replication phase) study. We included participants over 55 years of age to meet the age threshold for the modified Boston Criteria. The exposure was a diagnosis of CAA and the outcome was non-traumatic SDH, both identified using ICD-9 and ICD-10 codes. We used survival analyses with log-rank tests and multivariable Cox proportional hazards models adjusted for demographic characteristics and vascular risk factors. Results: The discovery phase included 283,452 UK Biobank participants comprising 123 CAA cases and 504 SDH cases. SDH subsequently occurred in 2.4% of participants with CAA versus 0.2% of those without CAA. In a multivariable Cox model, CAA was associated with a significantly increased risk of SDH (hazard ratio [HR], 7.3; 95% CI, 2.3-22.7). This finding was replicated among 168,370 study participants in All of US, where 66 had CAA and 443 had a SDH (HR, 11.66; 95% CI, 5.2-26.2). Conclusion: In two large heterogeneous cohorts conducted in different countries, CAA was independently associated with a higher risk of isolated non-traumatic SDH. Further research is needed to further determine causality and identify biological pathways that may mediate this association.

Cerebral amyloid angiopathy: clinical presentations and management challenges in the Australian context.

Cerebral amyloid angiopathy (CAA) is a disease with several clinical manifestations. It is characterised by amyloid-beta deposition in cerebral blood vessels, making them prone to bleeding. The incidence of CAA increases with age and may be associated or co-exist with intraparenchymal neurodegenerative proteinopathies, which makes it an increasingly relevant condition for adult physicians in all areas of medical practice. The vast majority of cases of CAA are sporadic with a small minority of familial cases. CAA is asymptomatic in many older adults but increases the risk of fatal intracerebral or subarachnoid haemorrhage. We review the existing literature on CAA and summarise the key findings. We specifically explore clinical challenges relevant to CAA, particularly in diagnosis, management of intracranial haemorrhage and management of concurrent medical conditions.

A case of cerebral amyloid angiopathy presented as subcortical brain hemorrhage in a young adult who underwent head trauma surgery using cadaveric dural graft in childhood

脳アミロイドアンギオパチー（CAA）は，55歳未満の発症は稀であり，その一部の症例において幼少期の脳外科手術との関連が報告されている．症例は，1歳時に頭部外傷手術に際して屍体硬膜を用いた硬膜再建を施行された37歳の男性．意識障害と運動性失語を認め，頭部CTで左側頭頭頂葉皮質下出血と診断された．脳血管撮影では，出血源となり得る有意所見は認めず，開頭血腫除去術を施行された．後日，創部感染から波及した左大脳実質の脳膿瘍に対して排膿術および骨弁除去術を施行され，その際に提出した脳表の病理組織診にて，血管壁へのアミロイドβ（Aβ）の沈着を認め，CAAの診断となった．CAAの遺伝的素因はなく，幼少期の屍体硬膜を用いた脳外科処置がAβの沈着とCAAの発症に関係していると考えられた．

An Elusive Case of Cerebral Amyloid Angiopathy: Diagnostic and Treatment Considerations.

An Elusive Case of Cerebral Amyloid Angiopathy: Diagnostic and Treatment Considerations.

Main features of hereditary cerebral amyloid angiopathies: A systematic review

The term Cerebral Amyloid Angiopathy (CAA) refers to a group of neurovascular disorders characterized by amyloid deposition within the walls of leptomeningeal and cortical blood vessels of the brain, with specific predilection for arterioles, and (less often) capillaries and veins. Most CAA cases in the general population are sporadic in nature, and represent primarily an age-related condition affecting individuals in the fifth decade of life and beyond. Sporadic CAA is caused by deposition of amyloid-β (Aβ), originating from proteolytic cleavage of the Amyloid Precursor Protein (APP), within the walls of cerebral small caliber vessels. However, hereditary forms of CAA have also been described, generally presenting as rare familial disorder with monogenic (predominantly autosomal dominant) inheritance patterns. Hereditary CAA forms tend to affect younger individuals, and their course and clinical progression is more severe. Studies to date primarily focused on the vascular manifestations of sporadic and hereditary CAA, chiefly symptomatic lobar Intracerebral Hemorrhage (ICH). However, in the past decade sporadic CAA has also been consistently linked to progressive neurocognitive, neurobehavioral, and neuropsychiatric symptoms. This systematic review focuses on the genetics, pathogenesis, neuroimaging, neuropathology, and clinical manifestations of hereditary CAA with specific emphasis on previously overlooked cognitive, behavioral, and psychiatric symptoms.

Cerebral amyloid angiopathy: early presentation in a patient with prior neurosurgical interventions

Background: Cerebral amyloid angiopathy (CAA) has classically been described as a disease of the elderly. Genetic predisposition has been linked to the APOE e3/e3 allele. Evidence suggests that brain insult in the form of injury, prior surgical intervention, or radiation can exacerbate the clearance of toxic proteins in patients susceptible to CAA. Case: We describe a unique case of CAA in a 30-year-old male who had prior surgical interventions for spina bifida, Chiari malformation, and hydrocephalus as a child. Conclusions: The case is used to teach important components regarding diagnosis, clinical suspicion, and highlight the need for further investigation regarding the emerging role of the glymphatic system and its role in clinical pathology.

Prion diseases, always a threat?

Prion disease is caused by prion which was identified as a causative factor of transmissible spongiform encephalopathy such as Creutzfeldt-Jakob disease (CJD) and means proteineaceous infectious particle. Prion diseases are devastating neurodegenerative disorders of human and many animals including sheep, cows, deer, cats and camels. CJD presents usually as a rapidly progressive dementia with other symptoms inevitably resulting in death often in months with no available therapy. Like other neurodegenerative diseases, prion diseases are classified into sporadic and genetic forms. In addition, there is the third category of environmentally acquired form. This type includes kuru and iatrogenic CJD due to human dura mater grafts or human pituitary derived hormones as well as variant CJD transmitted through food contaminated with prion of bovine spongiform encephalopathy (BSE). BSE and variant CJD has been almost controlled but chronic wasting disease, prion disease of deer, is spreading widely in North America and South Korea and recently in northern Europe. Recently Aß, α-synuclein and other proteins related to Alzheimer's, Parkinson's and other diseases were reported to have prion features such as transmission to animals. Aß transmission to human was suggested in iatrogenic CJD cases as well as in cerebral amyloid angiopathy cases with cerebral bleeding long after childhood neurosurgery with or without cadaveric dura. These findings indicate prion diseases due to various prions, namely various transmissible proteins appear to be a threat particularly in this longevity society. To overcome prion diseases is one of the top priority in our society.

A Scarlet Enemy of the Brain – A Practical Approach to Diagnosis and Management of Cerebral Amyloid Angiopathy

We present two cases of elderly patients admitted with neurological dysfunction due to isolated focal cortical subarachnoid bleeding and intracerebral lobar haemorrhage, respectively. We discuss the distinguishing features in their clinical and radiological presentations which led to their diagnosis of probable cerebral amyloid angiopathy (CAA). In the hope of encouraging thoughtful learning, we have designed a series of case-based questions with accompanying answers to explain the investigative pathways and management strategies in suspected cases of CAA.

Visuospatial dysfunction is associated with posterior distribution of white matter damage in non-demented cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a well-recognized contributor to cognitive decline in the elderly. The posterior cortical predilection of CAA pathology would cause visuospatial dysfunction, which is still underexplored. We aimed to investigate whether the visuospatial dysfunction in CAA is associated with the posterior distribution of small vessel disease (SVD) imaging markers. We recruited 60 non-demented CAA cases from a Chinese prospective cohort and 30 cases with non-CAA SVD as controls. We used the Visual Object and Space Perception (VOSP) battery to evaluate visuospatial abilities, and multivariable regression models to assess their associations with SVD imaging markers. There was visuospatial dysfunction, especially visual object perception impairment, in CAA compared to controls (Z-score of VOSP: -0.11±0.66 vs. 0.22±0.54, p=0.023). The VOSP score in CAA was independently related to the fronto-occipital gradient of white matter hyperintensity volumes (coefficient = 0.03, 95% confidence interval [CI] = 0.003-0.05, p=0.030) and mean fractional anisotropy values on diffusion tensor imaging (coefficient = 4.72, 95% CI = 0.97-8.48, p=0.015), but not the severity of global SVD imaging markers or the gradient of lobar cerebral microbleeds with adjustments for age and global cognition score. This finding suggests that the damage of posterior white matter rather than global disease severity may be a major contributor to visuospatial dysfunction in CAA.

Molecular Pathobiology of the Cerebrovasculature in Aging and in Alzheimers Disease Cases With Cerebral Amyloid Angiopathy.

Cerebrovascular dysfunction and cerebral amyloid angiopathy (CAA) are hallmark features of Alzheimer's disease (AD). Molecular damage to cerebrovessels in AD may result in alterations in vascular clearance mechanisms leading to amyloid deposition around blood vessels and diminished neurovascular-coupling. The sequelae of molecular events leading to these early pathogenic changes remains elusive. To address this, we conducted a comprehensive in-depth molecular characterization of the proteomic changes in enriched cerebrovessel fractions isolated from the inferior frontal gyrus of autopsy AD cases with low (85.5 ± 2.9 yrs) vs. high (81 ± 4.4 yrs) CAA score, aged-matched control (87.4 ± 1.5 yrs) and young healthy control (47 ± 3.3 yrs) cases. We employed a 10-plex tandem isobaric mass tag approach in combination with our ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method. Enriched cerebrovascular fractions showed very high expression levels of proteins specific to endothelial cells, mural cells (pericytes and smooth muscle cells), and astrocytes. We observed 150 significantly regulated proteins in young vs. aged control cerebrovessels. The top pathways significantly modulated with aging included chemokine, reelin, HIF1α and synaptogenesis signaling pathways. There were 213 proteins significantly regulated in aged-matched control vs. high CAA cerebrovessels. The top three pathways significantly altered from this comparison were oxidative phosphorylation, Sirtuin signaling pathway and TCA cycle II. Comparison between low vs. high CAA cerebrovessels identified 84 significantly regulated proteins. Top three pathways significantly altered between low vs. high CAA cerebrovessels included TCA Cycle II, Oxidative phosphorylation and mitochondrial dysfunction. Notably, high CAA cases included more advanced AD pathology thus cerebrovascular effects may be driven by the severity of amyloid and Tangle pathology. These descriptive proteomic changes provide novel insights to explain the age-related and AD-related cerebrovascular changes contributing to AD pathogenesis. Particularly, disturbances in energy bioenergetics and mitochondrial biology rank among the top AD pathways altered in cerebrovessels. Targeting these failed mechanisms in endothelia and mural cells may provide novel disease modifying targets for developing therapeutic strategies against cerebrovascular deterioration and promoting cerebral perfusion in AD. Our future work will focus on interrogating and validating these novel targets and pathways and their functional significance.

Abstract P342: Histopathological Correlates of MRI-Visible Perivascular Spaces in Cerebral Amyloid Angiopathy

Perivascular spaces (PVS) are fluid-filled spaces surrounding cerebral blood vessels. MRI-visible, supposedly enlarged, PVS in the centrum semiovale (CSO) have been associated with cerebral amyloid angiopathy (CAA). PVS enlargement may be due to perivascular clearance impairments, potentially caused by increased amyloid-β (Aβ) accumulation in the walls of vessels in the overlying cortex. We test this hypothesis, using MRI-guided histopathological examination of PVS in CAA autopsy cases. The cohort included 19 CAA (74.1±8.2y, 7F) and 5 non-CAA control cases (88.0±4.9y, 3F). Formalin-fixed hemispheres were scanned on a 3T MRI scanner, including a 500μm T2-weighted sequence. PVS enlargement was assessed in the CSO on in vivo and ex vivo MRI. In addition, local score of PVS enlargement was assessed in four pre-defined juxtacortical areas (Fig.A), using a semiquantitative score and on the corresponding histological sections (Fig.B). Severity of leptomeningeal and cortical CAA were assessed on adjacent Aβ-stained sections, using a semiquantitative scale.PVS enlargement was more severe in CAA cases compared to controls, both on in vivo and ex vivo MRI (p&lt;0.05). PVS enlargement on ex vivo MRI positively correlated with the severity of PVS enlargement on the corresponding histopathological samples (Fig.C). Within CAA cases, the degree of PVS enlargement on ex vivo MRI was positively associated with leptomeningeal CAA severity (n=52 samples, ρ=0.35, p=0.011), but not cortical CAA severity (n=52 samples, ρ=0.10, p=0.472). These preliminary findings confirm that the degree of MRI-visible PVS in juxtacortical brain areas reflects enlargement on histopathology. Moreover, they suggest that PVS enlargement in cases with CAA corresponds to increased CAA severity in the overlying leptomeningeal vessels, possibly as a result of impaired perivascular clearance. Future directions include characterization of individual blood vessels associated with PVS enlargement.

Detection of varicella zoster virus antigen and DNA in two cases of cerebral amyloid angiopathy

ObjectiveVaricella zoster virus (VZV) vasculopathy and cerebral amyloid angiopathy (CAA) have similar clinical presentations: both affect cerebrovasculature in the elderly, produce hemorrhage, and can have a protracted course of cognitive decline and other neurological deficits. The cause of CAA is unknown, but amyloid-beta (Aβ) is found within arterial walls. Recent studies show that VZV induces Aβ and amylin expression and an amyloid-promoting environment. Thus, we determined if VZV was present in CAA-affected arteries. MethodsTwo subjects with pathologically-verified CAA were identified postmortem and frontal lobes analyzed by immunohistochemistry for arteries containing VZV, Aβ, and amylin and H&E for pathological changes. VZV antigen detection was confirmed by PCR for VZV DNA in the same region. ResultsIn both CAA cases, sections with cerebral arteries containing VZV antigen with corresponding VZV DNA were identified; VZV antigen co-localized with Aβ in media of arteries with histological changes characteristic of CAA. Amylin was also seen in the intima of a VZV-positive artery in the diabetic subject. Not all Aβ-containing arteries had VZV, but all VZV-positive arteries contained Aβ. ConclusionsVZV antigen co-localized with Aβ in some affected arteries from two CAA cases, suggesting a possible association between VZV infection and CAA.

Comparison of Post-mortem 7.0-Tesla Magnetic Resonance Imaging of the Brains of Alzheimer Patients with and without Cerebral Amyloid Angiopathy

Purpose: The influence of cerebral amyloid angiopathy (CAA) in Alzheimer’s disease (AD) remains unexplored. The present post-mortem study investigated possible differences in the degree of hippocampal atrophy (HA) between AD patients with and without CAA using 7.0-tesla magnetic resonance imaging (MRI). Also, the incidence of the hippocampal cortical micro-infarcts (HCoMIs) and hippocampal cortical micro-bleeds (HCoMBs) is compared to those in the neocortex. Methods: The examined post-mortem brains included 30 AD-CAA cases and 20 AD without CAA cases. The samples of the hippocampus were evaluated on the most representative coronal section with T2 and T2* MRI sequences. The average degree of HA was determined in both groups. The incidences of HCoMIs and HCoMBs, along with the frequency of CoMIs and CoMBs in the neocortex were compared in both groups: AD-with CAA and AD without CAA cases. Results: No significant differences were observed in the degree of HA and the incidence of hippocampal micro-infarcts (HMIs) and hippocampal micro-bleeds (HMBs) between the AD-CAA and the AD brains in contrast to the higher incidence of these cerebrovascular lesions in the neocortex of AD-CAA brains. The incidence of CoMIs and CoMBs in the neocortex showed similarity to that in the hippocampus of AD patients without CAA. Conclusions: CAA does not influence the degree of HA and the incidence of micro-infarcts (MIs) and micro-bleeds (MBs) in the hippocampus, in contrast to the high contribution of the latter with CAA in the neocortex. The hippocampus seems to be more spared from cerebrovascular involvement than the other parts of the brain.