The 6th ICAA (International Cerebral Amyloid Angiopathy & related disorders) Association Conference was held in Lille from 6-8 September and it was really a wonderful and fruitful meeting. It was able to bring together the main experts in this field from several countries and the  neurologists/neuroradiologists/biotechnologists/researchers involved in the clinical management and in clinical and preclinical research about CAA in an interactive manner.

The program of the conference was well calibrated moving between basic research, translational issues, genetic and sporadic diseases, new treatment options and imaging, clinical, neuropsychological and biomarkers aspects of a phenotypically complex disease.

On day 1 (6th September) the morning session focused on the hereditary form of the disease, HCHWA-D.

The conference closely involved the patients’ association, that historically did a great contribute and impulse to the research about this condition and a representative from Dutch CAA Association introduced the talks about HCHWA-D, showing the great expectations of patients and relatives about the increased knowlege about the disease and the search of an effective therapy.

Dr. Sanneke van Rooden talked about Imaging markers of presymptomatic HCHWA-D patients, illustrating the findings of dedicated collaborative projects using high field MRI (3.0 and 7.0 T). Both in genetic and sporadic CAA the Increased CSO-PVS volume is a consistent magnetic resonance imaging marker of cerebrovascular amyloid deposition and a promising diagnostic tool for sporadic CAA without hemorrhagic manifestations. Moreover the identification of new disease markers on 7 T MRI (cortical changes and intragyral hemorrhage) in HCHWA-D may help recognizing sporadic cerebral amyloid angiopathy in living patients. The second speaker, Willeke van Roon, talked about an experimental treatment option, i.e. anti-sense oligonucleotide, to restore the right cleavage of APP; it is a promising way to counterbalance the cascade of events triggered by the gene mutation.

Another interesting and potentially relevant topic from a clinical point of view was discussed by Hyung Jin Ahn from New York, focusing on the binding affinity of β-amyloid’s for fibrinogen with relevant consequences (delayed fibrinolysis and fibrin deposit in the wall of small cerebral vessels). This finding could add an explanation to the increased hemorrhagic complications of CAA patients triggered by rtPA.

Another early imaging biomarker was proposed by Sophie Schmid from the Leiden group. She talked about the changes of cerebrovascular reactivity in HCHWA-D patients measured by CO2-challenge during visual tasks.

Milos Ikonomovic from Pittsburgh talked about the complex process of finding and testing a new PET tracer able to distinguish between parenchymal and vascular amyloid, showing the preliminary findings in animal model of the disease. Along the same line but in a clinical perspective in humans Jasmeer Chhatwal from Boston described the findings od a collaborative study focusing on PiB-PET in HCHWA-D patients, showing that PiB retention is increased by age and symptoms onset but this retention is lesser than in ADAD patients.

Changing type of hereditary CAA and talking about the Icelandic type due to Cystatin C mutation, Hakon Hakonarson proposed the approach of candidate gene therapy using N-acetylcysteine in 50 patients treated orally for 9 months with promising findings.

The Dementia Research Center of UCL (London) represented by Natalie S Ryan studied how the cerebral amyloid angiopathy influences clinical phenotype in familial Alzheimer’s disease, showing that patients with pyramidal and extrapyramidal signs have more CAA and cortical CAA is associated with cotton wool plaques severity.

Moreover, according to data presented by Lou Grangeon from Rouen, patients with APP duplications do not have significant differences in imaging markers in comparison with CAA patients without APP duplication.

Another hope for a new treatment went from Kawita Kanhai, who explored the feasibility of an active immunization clinical trial with a vaccine targeting amyloid-β vaccine in patients with HCHWA-D, with a practical approach similar to the immunotherapy in AD patients.

The second part of the day was dedicated to the biomarkers with several interesting presentations.

The first biomarkers examined are histopathological features of the disease; Konstantinos Arfanakis compared MRI and autopsy data in CAA patients coming from a population registry. One of the most relevant messages was that microbleeds have a PPV 0.48 in this community cohort, increasing the sensitivity of Boston criteria in this setting from a previous PPV 0.25.

Anand Viswanathan from Boston summarized the use and the potential future developments for PET imaging in sporadic CAA patients, hoping to have a dedecated tracer to vascular amyloid in the next future.

Another hot topic (Blood Brain barrier leakage in cerebral amyloid angiopathy) was introduced by Whitney M. Freeze from Boston, with a close comparison between post mortem MRI data and histopathology. The following speakers talked about the human transmission of amyloid β cerebral amyloid angiopathy from dural grafts and GH specimens (Zane Jaunmuktane) and the use of post processing of SWI MR images to derive a whole brain susceptibility map comparing AD and CAA patients (Valentina Perosa).

Marcel Verbeek provided us a complete and interesting overview about the state of the art of biomarkers in CAA and discussed the directions of future research sharing the objectives of recently approved research projects. A different and complementary approach was selected by Yael Reijmer, who presented the imaging marker of cognitive disfunction in CAA patients, focusing on contribution of CAA to cognitive decline and dementia. A novel biochemical signature of CAA is provided by blood metabolomics, discussed by Eric Smith from Calgary, showing promising data on a small subset of probable/possible CAA patients as preliminary findings to be confirmed in an ongoing project.

Hsin-Hsi Tsa from Taipei presented the application on Asian population of the topografic definition of cerebellar hemorrhage etiology recently suggested by MGH researchers.

The second day was dedicated to biological and physiological aspects in basic research, starting with experimental models of CAA to test the effect of biological variants of ApoJ and ApoA (Mar Hernandez-Guillamon from Barcelona), continuing with the vasoactive properties of amyloid β isoforms in CAA (Lieke Jäkel from Nijmegen) and the effect of microbleeds on cognition in mouse (Maud Pétrault from Lille), the role of Connexin 43 and Cx43 isoform lead in vascular injury (Anuska Andjelkovic from Ann Arbor) and the role of a new potential biomarker, Apolipoprotein D (H. Bea Kuiperij from Nijmegen).

The following talk was a very interesting presentation of an artificial vessel as a model for CAA e its potential application in research (Jérôme Robert from Vancouver), followed by a new animal model (transgenic rat) for CAA (William van Nostrand from Kingston) and the testing of a new potential treatment in the animal model (Gregory Bix from Lexington), ending the session with the demonstration in mice of the reuced vasoactivity related to the imparment of paravascular clearance of Abeta (Susanne J. van Veluw from Boston) and exploring the role of cerebrovascular smooth muscle cells in periarterial lymphatic drainage of the brain (Roxana Aldea from the University of Kentucky).

The second part of the day was dedicated to the clinical aspects of CAA, encompassing all manifestation of the disease and addressing the main clinical dilemmas in daily practice and the open questions about diagnosis and treatment of CAA patients to avoid incressing the ICH risk.

The first speaker (Rustam Al-Shahi Salman from Edinburgh) addressed the most relevant question, i.e. the anticoagulation in patients with possible/probabile CAA and atrial fibrillation both in ischemic and haemorrhagic presentation, summarizing the limited data provided by observational studies and concluding about the lacking of strong evidence to help the clinicians to make the right decision in individual cases. He concluded soliciting the enrollment of patients in ongoing trials.

The puzzle of indepentent contribution of CAA to cognitive impairment was composed by Jérémie Pariente (from Toulouse), presenting the relation of cognitive decline to individual MRI markers of CAA. About the same topic Géraldine Buard from Lille presneted the findings in an ancillary study of the BALTAZAR cohort.

A rare but underdiagnosed manifestation not only of CAA but also of AD is CAA-related inflammation and Fabrizio Piazza, cohordinator of an international multicenter project, the iCAB International Network, talked about the natural history of this disease presenting the long term follow-up of a huge cohort and addressing the effect of standard steroid treatment in the remission and recurrences of the disease. Yannick Chantran from Paris presented preliminary data about serum anti-Aβ antibody dosage in CAA-releted manifestations and the technical challenges of this technique in an interesting discussion with the previous speaker, who already developed a patent-registered technique for the same task. Auriel Eytan from Tel Aviv talked about the difficult clinical diagnosis and the application of the neuroimaging criteria for CAA-releted infammation published few years ago. Sonia Alamowitch from Paris reviewed the available data from literature about treatment of this manifestation.

Another practical and challenging topic was addressed in a clear way by Eric Smith from Calgary, i.e. transient focal neurological episodes. He started from the published data and proposed formal diagnosrtic criteria and an international registry about them and their role in CAA natural history.

The final day of the conference reserved intersting news and defined the future directions of the clinical research about CAA.

Mark Rodrigues from Edinburgh talked about the recently published CT-based criteria for CAA, presenting the ongoing external validation study of these criteria, being most contributors in the audience.

Frank Wollenweber from Munich illustrated cortical superficial siderosis in CAA, discussing about the diagnostic and rating criteria and the prognostic role of cSS in natural history of CAA. He also presented the ongoing SuSPECT-CAA study, specifically designed to address this last point.

The following presentations are focused on subarachnoid extension of lobar hemorrhage as marker of CAA (group of Dimitri Renard from Nimes), cSS progression (Thanakit Pongpitakmetha from Boston), cerebellar microbleeds distribution as potential marker of CAA-related cerebellar hemorrhage (Marco Pasi from Boston).

Jonathan Graff presented the findings of a community cohort, the Mayo Clinic Study of Aging, about the incidence of microbleeds and amyloid burden, showing as microbleeds are a common finding in aging. The group of Calgary presented the texture-based classification of white matter in CAA and healthy controls, showing a promising way to early identify microastructural damage in CAA.

Julie Schneider (from Chicago) shown the interesting autopsy data of aging population, widening the spectrum of cerebral diseases co-occurrence with aging and complicating the puzzle of a definite diagnosis in vivo.

Steven Greenberg from Boston did the conclusion of this wonderful conference, presenting the ongoing work about the updating of Boston criteria for CAA with the aim of including non-hemorrhagic presentations and validate them in several settings and not only in hospital based setting.

The next conference will be in Banff (Calgary) in 2020 and will be organized by Eric Smith.

Written by Marialuisa Zedde, Chair of ESO PR Committee