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The incidental evidence of white matter (WM) T2-hyperintense lesions on brain magnetic resonance imaging (MRI) is a clinical challenge. In a small subset of asymptomatic patients (less than 1%), lesions morphology and distribution are highly suggestive of multiple sclerosis (MS), hence meeting the disease dissemination in space criteria for the diagnosis of radiologically isolated syndrome (RIS). Conversely, in patients at first neurological presentation (clinically isolated syndrome [CIS]), prompt recognition of typical MS features and a correct application of McDonald criteria is fundamental for early diagnosis, and consequent disease-modifying treatments start. Despite large effort has been spent to better describe the clinical and MRI features typical of MS, it is estimated that about 20% of new MS diagnoses are incorrect, and explanations rely on clinical or radiological overlaps with mimicking disorders or improper interpretation of diagnostic criteria.

In both RIS and CIS patients concerns are related to their risk of clinical conversion to MS and future disability accrual. Evidence suggests that around 40% of CIS and 30% of RIS patients will develop MS over five years. These conditions share several predictors of disease evolution, such as younger age at presentation and the presence of spinal cord lesions.

In this lecture, we will examine the differential diagnosis of RIS and CIS patients, their clinical and MRI features, and current evidence about their prognosis.

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Subjective cognitive decline (SCD) is a relatively new term for a phenomenon that has been known and acknowlegded for many years. In older literature it was recognized as subjective complaints, known in the 1984 GDS staging as GDS 2, as well as studied in epidemiology research on aging extensively in then 90's. From that reserach it was knwon that people with SCD had a higher likelihood to progress to dementia, were more likely to carry an ApoE4 allel and should be paid attention to and being taken seriously by physicians.

The revival of the concept came with the extensive studies on biaomarkers of AD pathology using CSF and imaging. From these studies it became clear that in 10-20% of the cases of SCD, their complaints were caused by the presence of full blown AD pathology. This made the concept of SCD tangible and recognised as the preclinical stage of AD. With the boost in activities around drug development in AD, people with SCD are very interesting candidates to be put in clinical trials, as being the earliest stage of AD in vivo.

Meanwhile, operational definitions of SCD have been formulated and clinical recognition made possible, while a plethora of studies have shown which markers determine prgression to dementia.

In my talk, I will review all of the above and put them in te context of where we are in drug development of AD

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REM sleep behavior disorder (RBD) is a parasomnia characterized by loss of the normal paralysis of REM sleep, such that patient act out their dreams. It is strongly associated with neurodegenerative synucleinopathies, including PD, DLB and MSA. Of note, patients often present first with RBD (idiopathic/isolated RBD), and prospective studies suggest that >80% of iRBD patients will eventually develop a neurodegenerative disease, often 10-15 years post diagnosis. This presents a notable opportunity to intervene early in the process of neurodegeneration, before irreversible damage has occurred and (most notable for clinical trials) before symptomatic therapy confounds assessment of progression. In this talk, the diagnosis and treatment of RBD, and the potential of iRBD for the development of neuroprotective therapy against neurodegenerative synucleinopathy will be discussed.