Associations of Plasma Glutamatergic Metabolites with Alpha Desynchronization during Cognitive Interference and Working Memory Tasks in Asymptomatic Alzheimer's Disease.

Electroencephalogram (EEG) studies have suggested compensatory brain overactivation in cognitively healthy (CH) older adults with pathological beta-amyloid(Aß42)/tau ratios during working memory and interference processing. However, the association between glutamatergic metabolites and brain activation proxied by EEG signals has not been thoroughly investigated. We aim to determine the involvement of these metabolites in EEG signaling. We focused on CH older adults classified under (1) normal CSF Aß42/tau ratios (CH-NATs) and (2) pathological Aß42/tau ratios (CH-PATs). We measured plasma glutamine, glutamate, pyroglutamate, and γ-aminobutyric acid concentrations using tandem mass spectrometry and conducted a correlational analysis with alpha frequency event-related desynchronization (ERD). Under the N-back working memory paradigm, CH-NATs presented negative correlations (r = ~-0.74--0.96, p = 0.0001-0.0414) between pyroglutamate and alpha ERD but positive correlations (r = ~0.82-0.95, p = 0.0003-0.0119) between glutamine and alpha ERD. Under Stroop interference testing, CH-NATs generated negative correlations between glutamine and left temporal alpha ERD (r = -0.96, p = 0.037 and r = -0.97, p = 0.027). Our study demonstrated that glutamine and pyroglutamate levels were associated with EEG activity only in CH-NATs. These results suggest cognitively healthy adults with amyloid/tau pathology experience subtle metabolic dysfunction that may influence EEG signaling during cognitive challenge. A longitudinal follow-up study with a larger sample size is needed to validate these pilot studies.

Choriocapillaris and Retinal Vascular Alterations in Presymptomatic Alzheimer's Disease.

Purpose: To compare optical coherence tomography angiography (OCTA) retina metrics between cognitively healthy subjects with pathological versus normal cerebrospinal fluid (CSF) Aß42/tau ratios. Methods: Swept-source OCTA scans were collected using the Zeiss PLEX Elite 9000 and analyzed on 23 cognitively healthy (CH) subjects who had previously undergone CSF analysis. Thirteen subjects had a pathological Aß42/tau (PAT) ratio of <2.7132, indicative of presymptomatic Alzheimer's disease (AD), and 10 had a normal Aß42/tau (NAT) ratio of ≥2.7132. OCTA en face images of the superficial vascular complex (SVC) and deep vascular complex were binarized and skeletonized to quantify the perfusion density (PD), vessel length density (VLD), and fractal dimension (FrD). The foveal avascular zone (FAZ) area was calculated using the SVC slab. Choriocapillaris flow deficits (CCFDs) were computed from the en face OCTA slab of the CC. The above parameters were compared between CH-PATs and CH-NATs. Results: Compared to CH-NATs, CH-PATs showed significantly decreased PD, VLD, and FrD in the SVC, with a significantly increased FAZ area and CCFDs. Conclusions: Swept-source OCTA analysis of the SVC and CC suggests a significant vascular loss at the CH stage of pre-AD that might be an indicator of a neurodegenerative process initiated by the impaired clearance of Aß42 in the blood vessel wall and by phosphorylated tau accumulation in the perivascular spaces, a process that most likely mirrors that in the brain. If confirmed in larger longitudinal studies, OCTA retinal and inner choroidal metrics may be important biomarkers for assessing presymptomatic AD.