Welcome to the AD/PD™ 2022 Interactive Program

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Displaying One Session

Session Type
SYMPOSIUM
Date
Sun, 20.03.2022
Session Time
09:05 AM - 10:50 AM
Room
ONSITE: 112

COGNITIVE, EEG AND MRI FEATURES OF COVID-19 SURVIVORS: A 10-MONTH STUDY

Session Type
SYMPOSIUM
Date
Sun, 20.03.2022
Session Time
09:05 AM - 10:50 AM
Room
ONSITE: 112
Lecture Time
09:05 AM - 09:20 AM

Abstract

Aims

To explore cognitive, EEG and MRI features in COVID-19 survivors up to 10 months after hospital-discharge.

Methods

Adult patients with a recent diagnosis of COVID-19 underwent neuropsychological assessment and 19-channel-EEG within 2 months (baseline, N=49) and 10 months (follow-up, N=33) after hospital discharge. A brain MRI was obtained for 36 patients at baseline. Matched healthy controls were included. Using eLORETA, EEG regional current densities and linear lagged connectivity values were estimated. Total brain and white matter hyperintensities (WMH) volumes were measured. Clinical and instrumental data were evaluated between patients and controls at baseline, and within patient whole group and with/without dysgeusia/hyposmia subgroups over time. Correlations among findings at each timepoint were computed.

Results

At baseline, 53% and 28% of patients showed cognitive and psychopathological disturbances, respectively, with executive dysfunctions correlating with acute-phase respiratory distress. Compared to healthy controls, patients also showed higher regional current density and connectivity at delta band, correlating with executive performances, and greater WMH load, correlating with verbal memory deficits. A reduction of cognitive impairment and delta band EEG connectivity were observed over time, while psychopathological symptoms persisted. Patients with acute dysgeusia/hyposmia showed lower improvement at memory tests than those without. Lower EEG delta band at baseline predicted worse cognitive functioning at follow-up.

Conclusions

COVID-19 patients showed interrelated cognitive, EEG and MRI alterations 2 months after hospital discharge. Cognitive and EEG findings improved at 10 months. Dysgeusia and hyposmia during acute COVID-19 were related with increased vulnerability in memory functions over time.

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TRANSCRIPTOME SIGNATURES DRIVE SUSCEPTIBILITY TO SARS-COV-2 INFECTION IN ALZHEIMER´S DISEASE PATIENT-DERIVED OLFACTORY MUCOSAL CELLS

Session Type
SYMPOSIUM
Date
Sun, 20.03.2022
Session Time
09:05 AM - 10:50 AM
Room
ONSITE: 112
Lecture Time
09:20 AM - 09:35 AM

Abstract

Aims

Loss of olfaction is a long-term consequence of SARS-CoV-2 infection, suggesting viral invasion of the brain via the olfactory system. However, the underlying mechanisms remain unclear. This project utilizes a novel 3D in vitro model of the olfactory mucosa from non-demented individuals and Alzheimer’s disease (AD) patients to provide key insights into SARS-CoV-2 infection at this key entry site of airborne viruses.

Methods

We developed a 3D model consisted of primary human olfactory mucosal cells collected from nasal biopsies and cultured at air-liquid interface (ALI) (Fig 1). Cells grown for 21 days were infected with SARS-CoV-2 and cell phenotype and function were assessed. Infection was determined by viral RNA content and SARS-CoV-2 receptor expression by immunocytochemistry. Differential responses of healthy and AD-patient derived cells to SARS-CoV-2 were also determined by RNA-sequencing.

adpd_shahbaz.png

Results

Primary olfactory mucosal cells express several known SARS-CoV-2 receptors and are highly vulnerable to infection. AD-patient derived cells display alterations in susceptibility to infection, and in the cellular responses to the virus. RNA analyses revealed distinct profiles of susceptibility to infection and COVID19-associated biomarkers including cathepsins

Conclusions

Our data demonstrate that AD olfactory mucosal cells display a differential response to infection than healthy cells. These data provide important insight into the mechanisms of SARS-CoV-2 infection at a key entry point of airborne viruses. It also provides new targets for limiting or intervening with adverse effects of viral infection at the olfactory mucosa of AD patients.

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SARS-COV-2 ABILITY TO IMPACT SYNAPTOGENESIS IN NEURODEGENERATIVE DISORDERS USING THE HACE2 X 5XFAD MOUSE MODEL

Session Type
SYMPOSIUM
Date
Sun, 20.03.2022
Session Time
09:05 AM - 10:50 AM
Room
ONSITE: 112
Lecture Time
09:35 AM - 09:50 AM

Abstract

Aims

SARS-CoV-2 causes neurological complications in many people who have contracted COVID-19, with potential to exacerbate neurodegenerative pathologies. Our work showed the ability for SARS-CoV-2 to disrupt the blood-brain-barrier (BBB) in the hACE2 x 5xFAD mouse model, highlighting the ability for BBB leakage to adversely impact neural function. We aimed to better elucidate the impact of neural function by SARS-CoV-2, specifically as it related to Alzheimer’s disease (AD)-type neuropatholgy using the hACE2 x 5xFAD mouse model, and compared these findings to postmortem AD and SARS-CoV-2 infected brain tissue to determine the comparability to the human population.

Methods

Five month hACE2 x 5xFAD mice were intranasally inoculated with SARS-CoV-2 and sacrificed seven days post infection. Brain samples were collected for in situ hybridization (ISH) and RNAseq. Region matched postmortem AD + Sars+CoV-2 samples were processed for use with ISH and RNAseq. RNAseq data was analyzed using Ingenuity Pathway Analysis (IPA) and demonstrated differential regulation of pathways key to immune cell migration, BBB integrity, and synaptogenesis (adjusted p value< 0.01).

Results

SARS-CoV-2 creates neuroinflammation in hACE2 x 5xFAD following infection. SARS-CoV-2 mRNA is detectable in the cortex of the brain and localizes to specific cell types which we then compared to human tissue to uncover potential implications for SARS-COV-2 on AD cognitive deterioration via synaptic deterioration.

Conclusions

The hACE2 x 5xFAD mouse model provides a platform to study the effects of SARS-CoV-2 in AD-type cognitive decline leading to disruption of the BBB and ultimately loss of synaptic function.

Supported by the Altschul Foundation

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CONSTITUTIVELY ACTIVE STING CAUSES PROGRESSIVE DEGENERATION OF THE NIGROSTRIATAL NEURONS IN MICE: POTENTIAL RELEVANCE FOR LONG-COVID-19

Session Type
SYMPOSIUM
Date
Sun, 20.03.2022
Session Time
09:05 AM - 10:50 AM
Room
ONSITE: 112
Lecture Time
09:50 AM - 10:05 AM

Abstract

Aims

Chronic infections and neuroinflammation are with Parkinson`s disease (PD). The neuroinvasive coronavirus SARS-CoV-2 can induce neuronal injury, and neurological symptoms often present after viral clearance predicting long-term consequences of COVID-19 pandemic. Cytoplasmic nucleic acids (viral genome or miss-localized self-DNA), activate the stimulator of type I interferon genes (STING) pathway leading to the release of type 1 interferons (IFN) and proinflammatory cytokines. Here we tested whether prolonged STING activation causes PD-related neurodegeneration.

Methods

Activation of neuro-inflammatory pathways was confirmed in brains of COVID-19 patients. Gene expression, neuroinflammation, integrity of dopaminergic neurons and aSyn accumulation were quantified in brains of 5-week and 20-week old mice expressing the constitutive active genetic variant of STING (STING N153S/WT ki).

Results

Basal ganglia sections of COVID-19 patients showed microglia activation, increased microglial STING and nuclear pSTAT3 accumulation. Expression of interferon stimulated genes, IL-1b and IP-10 increased with age, as did nuclear accumulation of pSTAT3 and NFkB. In addition, 20-week-old mice showed significant degeneration of dopaminergic neurons in the substantia nigra and dopaminergic axon terminals in the striatum; striatal dopamine content was reduced. Furthermore, we observed the accumulation of aggregated aSyn in the striatum and a loss of striatal synapses. This phenotype was less pronounced when STING N153S/WT ki was expressed in mice with the additional knockout of the type I IFNα receptor, Caspase-1 or IP-10.

Conclusions

Our findings demonstrate that SARS-CoV-2 activates STING, and that chronic STING activation can induce degeneration of dopaminergic neurons. Blocking this pathway might prevent a potential surge in neurodegenerative diseases following the SARS-CoV-2 pandemic.

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GENOMIC CHARACTERIZATION OF HOST FACTORS RELATED TO SARS-COV-2 INFECTION IN PEOPLE WITH DEMENTIA AND CONTROL POPULATIONS: THE GR@ACE/DEGESCO STUDY.

Session Type
SYMPOSIUM
Date
Sun, 20.03.2022
Session Time
09:05 AM - 10:50 AM
Room
ONSITE: 112
Lecture Time
10:05 AM - 10:20 AM

Abstract

Aims

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study searching for susceptibility factors associated with COVID-19 disease.

Methods

To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom COVID-19 disease status was unknown. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We then performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative.

Results

We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20, OR=3.03[1.24-7.45], p=0.015) implicated in susceptibility to SARS-CoV-2 infection and TYK2 gene (OR=4.96[2.02-12.20], p=4.85×10-04) might be involved in COVID-19 severity. Meta-analysis supported the existence of other loci previously suggested for susceptibility to SARS-CoV-2 infection. In contrast, we were not be able to observe any evidence of statistically significant association, a compatible point effect nor consistent effect direction in the COVID-19 fatal outcome analysis adjusted by age and dementia status for APOE locus, in the stratified analyses using dementia-only or in non-dementia strata (Figure 1). 20210608_figure1_rev1.jpg

Conclusions

In conclusion, we confirmed the 3p21.31 region (LZTFL1, SLC6A20) and TYK2 gene as a genetic susceptibility locus involved in SARS-CoV-2 infection using an independent Spanish dataset. With COVID-19 HGI meta-analysis other suggested regions were reinforced. In contrast, our Dementia-only GWAS study did not support APOE locus involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.

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EXPLORING THE BASIS OF COVID-19-RELATED NEUROLOGICAL SEQUELAE: FIRST RESULTS FROM THE SAHLGRENSKA NEUROCOVID STUDY

Session Type
SYMPOSIUM
Date
Sun, 20.03.2022
Session Time
09:05 AM - 10:50 AM
Room
ONSITE: 112
Lecture Time
10:20 AM - 10:35 AM

Abstract

Aims

Patients with COVID-19 often report and present with a wide range of neurological symptoms, but the underlying mechanisms have only scarcely been characterised. The Sahlgrenska NeuroCOVID Study aims to map neurological sequelae in COVID-19 patients longitudinally with a focus on multi-domain cognitive impairment and associated processes using an array of modalities.

Methods

We will recruit 20 hospitalised COVID-19 patients (Group 1) who have either been treated with high-flow oxygen, several of which at the ICU (severe disease severity), or with oxygen (moderate), 20 convalescent patients (Group 2) with persisting neurological or cognitive symptoms and 20 age-matched healthy controls (HC). All subjects undergo comprehensive structural and functional MRI and [18F]FDG PET brain imaging, lumbar puncture, blood sampling and thorough neuropsychological examination including testing of olfactory and gustatory function. Group 1 will be examined on four occasions, Group 2 on two and HC on one over the 12-months course of the study.

Results

Preliminary findings from the hitherto recruited 19 patients from Group 1 (mean age 53.6 y, 7 females), 15 from Group 2 (mean age 46.9 y, 8 females) and 20 HC (mean age 53.7 y, 14 females) highlight the prevalence of subjective (subjective cognitive impairment and mental fatigue) and objectively assessed cognitive and psychological sequelae of COVID-19 affecting predominantly executive function, attention and speed domains.

Conclusions

There is a great need to understand the mechanisms underlying the multi-faceted long-term neurological consequences of COVID-19. We will present detailed 6-months data focusing on the relationship between cognitive performance and bodily fluid- and neuroimaging-derived biomarkers.

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DISCUSSION

Session Type
SYMPOSIUM
Date
Sun, 20.03.2022
Session Time
09:05 AM - 10:50 AM
Room
ONSITE: 112
Lecture Time
10:35 AM - 10:50 AM