Discovery and characterization of novel indole and 7-azaindole derivatives as inhibitors of ß-amyloid-42 aggregation for the treatment of Alzheimer's disease.

The aggregation of amyloid-ß peptides into cytotoxic oligomeric and fibrillary aggregates is believed to be one of the major pathological events in Alzheimer disease. Here we report the design and synthesis of a novel series of indole and 7-azaindole derivatives containing, nitrile, piperidine and N-methyl-piperidine substituents at the 3-position to prevent the pathological self-assembly of amyloid-ß. We have further demonstrated that substitution of the azaindole and indole derivatives at the 3 positions is required to obtain compounds with improved physicochemical properties to allow brain penetration.

Synthesis and structure-activity relationship of 2,6-disubstituted pyridine derivatives as inhibitors of ß-amyloid-42 aggregation.

It is assumed that amyloid-ß aggregation is a crucial event in the pathogenesis of Alzheimer's disease. Novel 2,6-disubstituted pyridine derivatives were designed to interact with the ß-sheet conformation of Aß via donor-acceptor-donor hydrogen bond formation. A series of pyridine derivatives were synthesized and tested regarding their potential to inhibit the aggregation of Aß. The 2,6-diaminopyridine moiety was identified as a key component to inhibit Aß aggregation. Overall, compounds having three 2,6-disubstituted pyridine units separated by at least one C2- or C3-linker displayed the most potent inhibition of Aß aggregation.

The Prognostic Value of Olfactory Dysfunction in Patients with COVID-19: The COVIDORA Study.

BACKGROUND: Among all studies describing COVID-19 clinical features during the first wave of the pandemic, only a few retrospective studies have assessed the correlation between olfac-tory dysfunction (OD) and the evolution of disease severity. The main aim was to assess whether OD is a predictive factor of COVID-19 severity based on the patient's medical management (outpa-tient care, standard hospital admission, and ICU admission). METHODS: A national, prospective, mul-ticenter cohort study was conducted in 20 public hospitals and a public center for COVID-19 screen-ing. During the first wave of the pandemic, from 6 April to 11 May 2020, all patients tested positive for COVID-19 confirmed by RT-PCR underwent two follow-up ENT consultations within 10 days of symptom onset. The main outcome measures were the evolution of medical management (out-patient care, standard hospital admission, and ICU admission) at diagnosis and along the clinical course of COVID-19 disease. RESULTS: Among 481 patients included, the prevalence of OD was 60.7%, and it affected mostly female patients (74.3%) under 65 years old (92.5%), with fewer comor-bidities than patients with normal olfactory function. Here, 99.3% (290/292) of patients with OD presented with non-severe COVID-19 disease. Patients reporting OD were significantly less hospi-talized than the ones managed as outpatients, in either a standard medical unit or an ICU. Conclu-sions: As regards the clinical course of COVID-19 disease, OD could predict a decreased risk of hospitalization during the first wave of the pandemic.

Loss of smell in patients with COVID-19: MRI data reveal a transient edema of the olfactory clefts.

OBJECTIVE: To assess the physiopathology of olfactory function loss (OFL) in patients with coronavirus disease 2019 (COVID-19), we evaluated the olfactory clefts (OC) on MRI during the early stage of the disease and 1 month later. METHODS: This was a prospective, monocentric, case-controlled study. Twenty severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)-infected patients with OFL were included and compared to 20 age-matched healthy controls. All infected patients underwent olfactory function assessment and 3T MRI, performed both at the early stage of the disease and at the 1-month follow-up. RESULTS: At the early stage, SARS-CoV2-infected patients had a mean olfactory score of 2.8 ± 2.7 (range 0-8), and MRI displayed a complete obstruction of the OC in 19 of 20 patients. Controls had normal olfactory scores and no obstruction of the OC on MRI. At the 1 month follow-up, the olfactory score had improved to 8.3 ± 1.9 (range 4-10) in patients, and only 7 of 20 patients still had an obstruction of the OC. There was a correlation between olfactory score and obstruction of the OC (p = 0.004). CONCLUSION: OFL in SARS-CoV2-infected patients is associated with a reversible obstruction of the OC.

Self-reported loss of smell without nasal obstruction to identify COVID-19. The multicenter Coranosmia cohort study.

OBJECTIVES: To determine the frequency of SARS-CoV-2 positive samples in a subset of patients consulting for primarily isolated acute (<7 days) loss of smell and to assess the diagnostic accuracy of olfactory/gustatory dysfunction for COVID-19 diagnosis in the overall population tested for COVID-19 in the same period. METHODS: Prospective multicentric cohort study in four olfactory ENT units and a screening center for COVID-19. RESULTS: i) Among a subset of 55 patients consulting for primarily recent loss of smell, we found that 51 (92.7%) had a COVID-19 positive test (median viral load of 28.8 cycle threshold). Loss of smell was mostly total (anosmia), rarely associated with nasal obstruction but associated with a taste disorder in 80%. Olfactory dysfunction occurred suddenly, either as first complaint or preceded by mild symptoms occurring a median of 3 days. The majority of patients (72.9%) partially recovered the sense of smell within 15 days. ii) In a population of 1824 patients tested for COVID-19, the positive predictive value and the specificity of loss of smell and/or taste were 78.5% and 90.3% respectively (sensitivity (40.8%), negative predictive value (63.6%)). CONCLUSIONS: Self-reported loss of smell had a high predictive positive value to identify COVID-19. Making this sign well known publicly could help to adopt isolation measures and inform potential contacts.