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EEG FINDINGS IN A PHASE 2 STUDY OF THE ORAL P38Α KINASE INHIBITOR NEFLAMAPIMOD IN PATIENTS WITH MILD-TO-MODERATE DEMENTIA WITH LEWY BODIES (DLB)

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
02:45 PM - 05:15 PM
Room
Onsite - Hall E
Lecture Time
04:30 PM - 04:45 PM

Abstract

Aims

Neflamapimod targets pathogenic mechanisms considered to underlie basal forebrain cholinergic (BFC) neurodegeneration, a major driver of dementia in DLB. In a recent phase 2 study in mild-to-moderate DLB (“AscenD-LB”), neflamapimod demonstrated clinically meaningful improvement in cognition (DLB-specific Neuropsychological Test Battery) and function (Timed-Up-and-Go Test). Here, we provide the EEG results from this study.

Methods

Neflamapimod (40 mg) or placebo was administered BID or TID for 16 weeks. Task-free, eyes-closed EEG was performed at baseline and week 16. Due to COVID-19, week 16 EEG assessments were only available in 29 of 91 patients. Quantitative EEG analysis involved functional connectivity analysis in canonical frequency bands, more specifically the corrected Amplitude Envelope Correlation (AECc). 2-sided Wilcoxon Rank Sum Test p-values are reported.

Results

Overall, a consistent trend towards improved functional connectivity was found in the treated group. Mean AECc in the beta band (13-30 Hz) significantly increased with neflamapimod TID vs all placebo (p=0.033) and vs placebo TID (p=0.01). The effect was most prominent in the frontal region (p=0.009 for placebo TID vs neflamapimod TID), and in the lower beta range (13-20 Hz).

Conclusions

In this modest cohort size, neflamapimod shows a positive effect on beta band functional connectivity. The effect is dose-dependent and most pronounced in the 40mg TID dose group, which previously also showed the clinical effects. Since impaired functional connectivity in the beta band is a known and relatively specific DLB finding, these results imply functional recovery. A follow-up clinical study will explore the observed treatment effects on EEG in a larger cohort.

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INCREASED PRESENCE OF PHOSPHORYLATED TAU IN THE RETINA OF ALZHEIMER’S DISEASE AND OTHER TAUOPATHIES

Session Type
SYMPOSIUM
Date
Fri, 18.03.2022
Session Time
02:45 PM - 04:45 PM
Room
Onsite - Hall C
Lecture Time
03:30 PM - 03:45 PM

Abstract

Aims

There is increased interest in in vivo labeling of Alzheimer’s disease (AD) pathology in the retina as a non-invasive, low-cost diagnostic approach. In this study we assessed the presence of different tau isoforms in post-mortem retinas of AD and controls, as well as other neurodegenerative diseases associated with or without tau pathology.

Methods

Post-mortem eyes were collected through the Netherlands Brain Bank from donors with AD (n=17), frontotemporal lobar degeneration (FTLD; n=6), other tauopathies (n=7), alpha-synucleinopathies (n=13), as well as non-neurodegenerative controls (n=16) and other neurodegenerative cases (n=3). Cross-sections of the superior-temporal quadrants were immunostained for total tau (HT7), early tau phosphorylation (AT8, AT100, AT270), 3R and 4R tau isoforms (RD3/RD4) and late tau phosphorylation (pS422).

Results

Total tau (HT-7) was observed in all cases. The presence of 3- and 4-repeat isoforms of tau varied within the inner plexiform layer (IPL) and outer plexiform layer (OPL) with more 3-repeat tau in the IPL and more 4-repeat tau in the OPL. In general, AD and other tauopathy cases showed positive immunoreactivity for AT8. Tau phosphorylated at Ser422 was negative in all groups.

Conclusions

In controls with cerebral cortical tau and neurodegenerative tauopathy cases, high levels of tau are present in the retina, mainly in the plexiform layers. Overall, tau phosphorylated at Ser202/Thr205 differentiates tauopathies from other neurodegenerative diseases and non-neurodegenerative controls. Depending on the epitope, phosphorylated tau is a potential retinal biomarker for AD and other tauopathies.

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