APP Mutations in Cerebral Amyloid Angiopathy with or without Cortical Calcifications: Report of Three Families and a Literature Review

Sellal, François; Wallon, David; Martinez-Almoyna, L.; Marelli, Cécilia; Dhar, Abhinav; Oesterlé, Hélène; Rovelet‐Lecrux, Anne; Rousseau, Stéphane; Kourkoulis, Christina; Rosand, J; DiPucchio, Zora; Frosch, Matthew P.; Gombert, Claudine; Audoin, Bertrand; Miné, Manuèle; Riant, Florence; Frébourg, Thierry; Hannequin, Didier; Campion, Dominique; Greenberg, Steven M.; Tournier‐Lasserve, Elisabeth; Nicolas, Gaël

doi:10.3233/jad-160709

Cited by 34 publications

(27 citation statements)

References 29 publications

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“…Despite the spatial correlation between CAA load and vascular calcification, to date there is no proof for causality between the presence of the Aβ peptide per se, and calcification of the vessel wall . This is further supported by our previous finding where we observed calcification of non‐CAA vessels in a sCAA case .…”

Section: Discussionsupporting

confidence: 69%

“…Similar calcifications have been observed in other hereditary CAA variants, such as the Iowa and Italian variants (26,33,44). In sporadic CAA, calcification of cortical areas involving CAA-affected vessels seems to be much rarer than in the familial cases; its has only been described in three cases of CAA-associated cerebral hemorrhage (5,20,28).…”

Section: Introductionsupporting

confidence: 79%

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Osteopontin and phospho‐SMAD2/3 are associated with calcification of vessels in D‐CAA, an hereditary cerebral amyloid angiopathy

et al. 2019

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In severe forms of cerebral amyloid angiopathy (CAA) pathology, vascular calcification has been observed in the cerebral cortex, both in vivo on MRI and CT, and post‐mortem using histopathology. However, the pathomechanisms leading to calcification of CAA‐laden arteries are unknown. Therefore, we investigated the correlation between calcification of cortical arterioles and several potential modulators of vascular calcification using immunohistochemistry in a unique collection of brain material of patients with a hereditary form of CAA, namely hereditary cerebral hemorrhage with amyloidosis‐Dutch type (HCHWA‐D or D‐CAA). We show a topographical association of osteopontin (OPN) and TGFβ signaling factor phospho‐SMAD2/3 (pSMAD2/3) in calcified CAA vessel walls. OPN and pSMAD2/3 gradually accumulate in vessels prior to calcification. Moreover, we found that the vascular accumulation of Collagen 1 (Col1), OPN and pSMAD2/3 immunomarkers correlated with the CAA severity. This was independently of the vessel size, including capillaries in the most severe cases. We propose that calcification of CAA vessels in the observed HCHWA‐D cases may be induced by extracellular OPN trapped in the fibrotic Col1 vessel wall, independently of the presence of vascular amyloid.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionsupporting

confidence: 79%

Osteopontin and phospho‐SMAD2/3 are associated with calcification of vessels in D‐CAA, an hereditary cerebral amyloid angiopathy

et al. 2019

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“…In addition, 5 subjects from 3 families carried mutations located within the coding sequence of the Aβ peptide: one carried the “Flemish” APP mutation c.2075C>G, p.(Ala692Gly), two carried the “Italian” mutation c.2077G>A, p.(Glu693Lys), and another two carried the “Iowa” mutation c.2080G>A, p.(Asp694Asn). A complete description of the phenotype of these 5 patients is provided in Sellal et al [19]. …”

Section: Resultsmentioning

confidence: 99%

“…Adding this sample to our previous reports [1,8,9,14,15,19,21–24], a total of 170 AD-EOAD families and 18 sporadic cases carrying mutations in genes known to cause EOAD have now been identified by our national reference center. Ninety distinct mutations (78 PSEN1 , 4 PSEN2 , and 8 APP , including APP duplication) were represented by respectively 127, 9, 34, and 18 occurrences in this whole sample (S1 Table).…”

Section: Resultsmentioning

confidence: 99%

APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases

et al. 2017

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BackgroundAmyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.Methods and findingsWe report here a novel update (2012–2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers—total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42—in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.ConclusionsOur findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.

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“…Higher incidences of brain calcifications are found in patients with neurodegenerative diseases such as Alzheimer's disease (AD) [37,38], cerebral amyloid angiopathy [4], frontotemporal dementia (FTD) [36], Parkinson's disease and Down syndrome [68]. Calcified deposits in the human brain are also found distributed throughout the hippocampus and basal ganglia, and some are associated with cerebral vessels and cerebral amyloid angiopathy [7,9,15,20,57]. In patients with diffuse neurofibrillary tangles with calcification, pallidal calcification is the most prominent feature and is accompanied by frontotemporal atrophy, neurofibrillary tangle (NFT) deposition throughout the neocortex, without the occurrence of β -amyloid plaques [30].…”

Section: Introductionmentioning

confidence: 99%

Tau deposition is associated with imaging patterns of tissue calcification in the P301L mouse model of human tauopathy

Zarb

Kuhn

et al. 2019

Preprint

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Brain calcification is associated with several neurodegenerative proteinopathies. Here, we report a new phenotype of intracranial calcification in transgenic P301L mice overexpressing 4 repeat tau. P301L mice (Thy1.2) of 3, 5, 9 and 18-25 months-of-age and age-matched non-transgenic littermates were assessed using in vivo/ex vivo magnetic resonance imaging (MRI) with a gradient recalled echo sequence and micro computed tomography (μCT). Susceptibility weighted images computed from the gradient recalled echo data revealed regional hypointensities in the hippocampus, cortex, caudate nucleus and thalamus of P301L mice, which in corresponding phase images indicated diamagnetic lesions. Concomitantly, µCT detected hyperdense lesions.Occurrence of diamagnetic susceptibility lesions in the hippocampus, increased with age.Immunochemical staining of brain sections revealed bone protein-positive deposits. Furthermore, intra-neuronal and vessel-associated protein-containing nodules co-localized with phosphorylated-tau (AT8 and AT100) in the hippocampus. Protein-containing nodules were detected also in the thalamus in the absence of phosphorylated-tau deposition. In contrast, osteocalcin-containing nodules were vessel-associated, indicating ossified vessels, in the thalamus in absence of phosphorylated-tau. In summary, MRI and µCT demonstrated imaging pattern of intracranial calcification, concomitant with immunohistochemical evidence of formation of protein deposits containing bone proteins along with phosphorylated-tau in the P301L mouse model of human tauopathy. The P301L mouse model may thus serve as a future model to study the pathogenesis of brain calcifications in tauopathies.3

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APP Mutations in Cerebral Amyloid Angiopathy with or without Cortical Calcifications: Report of Three Families and a Literature Review

Abstract: This is the first evidence of cortical calcification in patients with an APP mutation other than the Iowa mutation. We discuss the radiological, cerebrospinal fluid, and clinical phenotype of patients carrying these mutations in the literature.

Cited by 34 publications

References 29 publications

Osteopontin and phospho‐SMAD2/3 are associated with calcification of vessels in D‐CAA, an hereditary cerebral amyloid angiopathy

Osteopontin and phospho‐SMAD2/3 are associated with calcification of vessels in D‐CAA, an hereditary cerebral amyloid angiopathy

APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases

Tau deposition is associated with imaging patterns of tissue calcification in the P301L mouse model of human tauopathy

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