Download Cerebral Amyloid Angiopathy Criteria The Next Generation Pdf ##HOT##
This case report describes fulminant eosinophilic meningitis and vasculitis with multifocal strokes and intracranial hypertension caused by ABRA. To our knowledge, this is the first reported case where the eosinophilic pleocytosis is associated with intracranial hypertension resulting in papilledema, and the third reported case of eosinophilic meningitis due to ABRA [4, 5]. In the first case in the literature, the patient presents with a lobar hemorrhage prompting consideration of cerebral amyloid angiopathy (CAA), then re-presents with subacute cognitive decline and aphasia . The second case is described as eosinophilic meningitis due to primary angiitis of the central nervous system (PACNS), although the biopsy demonstrates a diagnosis of ABRA . Our case further emphasizes that ABRA should be added to the differential diagnosis of eosinophilic meningitis (Table 1), while also demonstrating the variable clinical presentation of the disease by describing an unusual and severe syndrome. In all three cases, eosinophilia was isolated to the CSF, helping to distinguish ABRA from other causes of eosinophilic meningitis that commonly include peripheral eosinophilia . Additionally, all three patients had stabilization but not resolution of symptoms at the time of treatment, illustrating the importance of an early diagnosis. ABRA is important to include in the differential for eosinophilic meningitis because, unlike infectious causes which may worsen with immunosuppression, ABRA is typically responsive to immunosuppression and most patients have a positive outcome if treated early [3, 6, 7].
Download Cerebral amyloid angiopathy criteria the next generation pdf
A 76-year-old female with symptomatic left carotid stenosis (70% by North American Symptomatic Carotid Endarterectomy Trial criteria) who presented with right homonymous hemianopia compatible with a left posterior cerebral artery stroke. Arterial spin labeling demonstrates hypoperfusion throughout the left cerebral hemisphere (a) and CTA demonstrates a fetal left posterior cerebral artery supplied by the left internal carotid artery (b). Florbetaben PET/CT demonstrates no to sparse amyloid plaque (c). Flortaucipir PET/CT prior to the event demonstrates no areas of cortical tau retention (d). Flortaucipir PET/CT following the event (e) demonstrates focal tau retention in the left posterior cerebral artery territory (arrows), likely as a response to cerebral ischemia
Attention has recently focused on the relatively rare leptomeningeal form of TTR amyloidosis, which is induced by several point mutations in the TTR gene and also found in the advanced stages of Val30Met TTR-FAP . In most cases, it is believed that the source of variant TTR in leptomeningeal amyloidosis is not the liver but the choroid plexus . Cerebral amyloid angiopathy and ocular amyloidosis are common clinical features of this type of TTR amyloidosis. Cerebral amyloid angiopathy is characterized by amyloid deposition in the media and adventitia of medium-sized and small arteries, arterioles, and, occasionally, veins of the cortex and leptomeninges. Typical clinical central nervous system manifestations include cerebral infarction and hemorrhage, hydrocephalus, ataxia, spastic paralysis, convulsion, and dementia. These symptoms are often found in several types of TTR amyloidosis and they lead to the classification of (oculo)leptomeningeal amyloidosis, in which amyloid deposition is also found in vitreous bodies and other tissues of the eye. Although amyloid deposits in the meningocerebrovascular system are thought to be the cause of those central nervous system symptoms, the precise mechanism of amyloid formation remains to be elucidated.
Unfortunately the next generation of drugs acting on AD core pathological factors such as amyloid deposition and phosphorylated tau aggregation has failed so far to delay disease progression, raising the issue of timing of these interventions along the continuum of AD neurodegeneration over time.
Most AD patients have structural changes in their cerebral blood vessels. Imaging and pathological studies have demonstrated a high prevalence of arteriolosclerotic small vessel disease (SVD) in AD patients. Post-mortem and imaging studies demonstrate that arteriolar Aβ amyloid angiopathy, a sub-type of SVD, is more common in patients with AD than in elderly controls [19,20,21,22,23]. The amyloid angiopathy mainly affects the leptomeningeal, cortical and capillary vessel walls, but sometimes the cerebellum, and occasionally the brainstem [12, 24]. In the autopsy studies, it suggests that AD is correlated with atherosclerosis of the Circle of Willis, and the severity of the atherosclerosis is associated with neuritic plaques and neurofibrillary tangles [25,26,27].
An important component of CVD in AD is cerebral hypoperfusion, which can be present several years before the onset of clinical symptoms. The diffusion pattern of cerebral hypoperfusion is stereotyped in AD: the first affected area of is the precuneus, which has appeared 10 years before the onset of AD, followed by the cingulate gyrus and the lateral part of the parietal lobe, then the frontal and temporal lobes, and the eventually the cerebrum . The main mechanism of cerebral hypoperfusion in AD may be non-structural . In vivo and in vitro studies have shown cerebral hypoperfusion increases the production of Aβ and tau hyperphosphorylation, reduces the clearance of Aβ, then aggravates the progress of AD [28,29,30,31,32,33]. There is good evidence that Aβ amyloid angiopathy and SVD are associated with infarction and cerebral hemorrhage in AD [34,35,36,37,38,39,40,41,42,43]. The mechanisms may involve susceptibility to thrombosis, reduction of blood flow, impaired caliber regulation, and impaired function of the blood-brain barrier (BBB). Infarction or bleeding will reduce the threshold for the onset of AD, and is considered as an important risk factor for the clinical manifestations of AD [44, 45].
CAA is a common cerebral small vessel disease of elderly people, a prominent feature of AD, and a cause of VCID. However, our understanding of the etiology and downstream pathological consequences of cerebral vascular amyloid accumulation are still limited resulting in a lack of effective therapeutic treatments. Therefore, valid and consistent preclinical animal models to study the pathogenesis of CAA are paramount. Most previous animal studies on CAA involved the use of various human AβPP transgenic mouse models that develop variable levels of CAA in the presence or absence of parenchymal amyloid pathology [41,42,43,44]. Recently, we reported the generation of a novel transgenic rat model (rTg-DI) that robustly develops capillary CAA type-1 . We showed that rTg-DI rats express low amounts of human chimeric Dutch (E22Q)/Iowa (D23N) familial CAA mutant Aβ in the brain and develop early-onset and progressive microvascular CAA. As CAA progresses in rTg-DI rats, they develop consistent and numerous cerebral microbleeds that can readily be detected by magnetic resonance imaging. These findings suggest that rTg-DI rats have the potential to be a useful preclinical platform to study the pathogenesis of CAA type-1, to identify biomarkers for disease and to test therapeutic interventions. Indeed, we recently showed that decreasing levels of Aβ40 peptide in cerebrospinal fluid correlated with the progression of CAA in this model . To better understand the utility of rTg-DI rats as a valid preclinical model, here we investigated the temporal development of several perivascular pathologies that are commonly observed with human CAA type-1. Our results show that with the progression of cerebral microvascular amyloid deposition, rTg-DI rats develop robust perivascular neuroinflammation, disruption and loss of capillary pericytes, increased numbers of caspase 3-positive cells, and disruption of axonal integrity. These findings indicate that rTg-DI rats faithfully recapitulate many of the pathological features of human CAA type-1 and provide new insight into the pathogenesis of this condition.
The rTg-DI rat is a novel model of early-onset and progressive cerebral microvascular amyloid deposition that recapitulates many features of human CAA type-1. Our results show that there is a relationship between the onset and progressive accumulation of cerebral microvascular amyloid with the temporal development of neuroinflammation and perivascular cellular pathology. Advanced stages of microvascular amyloid and neuroinflammation in rTg-DI rats is associated with pronounced pericyte loss in capillaries, degeneration of astrocytes, and disruption of neuronal axonal integrity. These findings underscore the utility of rTg-DI rats to serve as a useful preclinical platform to develop biomarkers and to test therapeutic strategies to intervene in the onset and progression of microvascular CAA and its role in VCID.
Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimers disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition. 041b061a72