KaRaMinds

BackgroundCSF and blood soluble TREM2 (sTREM2) levels have been found to increase at early stage of Alzheimer's disease (AD). The relationships between sTREM2, AD-related biomarkers, and other neuroinflammation biomarkers remain unclear. Moreover, the impact of rare variants in TREM2 gene (R47H/R62H), which are associated with increased risk of AD, on plasma sTREM2 has not been elucidated.ObjectiveInvestigate the association of plasma sTREM2 levels with brain amyloid-β (Aβ) load and AD-related blood biomarkers, i.e., phosphorylated tau (pTau)-181, pTau-231, GFAP, NFL, and other neuroinflammation and peripheral inflammation markers in cognitively normal (CN) older adults at risk of AD (CN Aβ+) compared to CN Aβ-, including the effect of AD-linked TREM2 rare variants.MethodsPlasma sTREM2 concentrations were measured by MesoScale Discovery (MSD) assay from the KARVIAH cohort. Participants underwent cognitive tests and PET amyloid imaging. Genetic data and blood biomarkers were included for correlation analysis. Associations with plasma sTREM2 were investigated upon stratification by PET-Aβ load SUVR ((CN Aβ- (n = 65) and CN Aβ+ (n = 35)) as the main analysis. A subgroup analysis based on the TREM2 R47H and R62H genotype was conducted as exploratory analysis.ResultsPlasma sTREM2 positively correlated with plasma pTau181, and pTau231 in CN Aβ+ group. Plasma sTREM2 positively correlated with serum microglial kynurenine pathway metabolites. Plasma sTREM2 and brain Aβ load were higher in R47H TREM2 carriers compared to non-carriers.ConclusionsOur findings suggest plasma sTREM2 relates to downstream tau processes in amyloid-positive individuals, providing novel insights into the roles of peripheral TREM2 signaling that reflects microglial activity in early AD neuropathological development.

Abstract BackgroundResearch on cognitive reserve (CR) in individuals aged 80 years old and above has resulted in inconsistent findings, mostly showing a relationship with baseline cognitive abilities but not follow up assessments. The effects of amyloid burden on the relationship between CR, cognitive decline and dementia in oldest old warrants further study in the presence of APOE e4. We hypothesised that CR in oldest old (≥80 yrs old) adults will result in different trajectories, depending on being amyloid PET positive or negative. Specifically, this study was to determine whether the relationship between CR and cognition is mediated by amyloid load in very old individuals.MethodData of 115 participants aged 80 years and above at baseline and one follow‐up was analysed for this study. Participants were recruited from the Western Australia Memory Study (WAMS, Perth) and the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) Study (Sydney, Australia). In both sites participants have undergone amyloid imaging, as well as a comprehensive neuropsychological assessment, APOE genotyping and AD‐related blood‐based biomarkers analysis.ResultPreliminary results indicated a non‐significant relationship between education years, as the proxy for CR, and baseline cognition. Similar not‐significant findings was observed between CR and amyloid load. Individuals positive or negative for amyloid burden on the brain at baseline, as well as carriage of APOE e4 did not differ on years of education. Of interest, APOE e4 allele carriers were not different from not‐carriers on amyloid load in the brain. Due to nonsignificant relationships between the variables of interest, in both cross‐sectional as well as longitudinal data, further mediation analysis was not carried out.ConclusionOur nonsignificant results indicated that the commonly reported relationship between CR, cognitive function, amyloid load in older adults may not be present in individuals aged 80 years old and above. Although these findings are consistent with previous reports, other factors including longevity genetic factors that promote preserving cognition in oldest adults as well as lifestyle factors should be considered. Further analysis of such factors is currently ongoing and may result in interesting outcomes for this cohort.

The disruption of neurofilament, an axonal cytoskeletal protein, in neurodegenerative conditions may result in neuronal damage and its release into the cerebrospinal fluid and blood. In Alzheimer's disease (AD), neurofilament light chain (NFL), a neurofilament subunit, is elevated in the cerebrospinal fluid and blood. Investigate the association of plasma NFL with preclinical-AD features, such as high neocortical amyloid-β load (NAL) and subjective memory complaints, and cognitive performance in cognitively normal older adults. Plasma NFL concentrations were measured employing the single molecule array platform in participants from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort, aged 65- 90 years. Participants underwent a battery of neuropsychological testing to evaluate cognitive performance and were categorized as low NAL (NAL-, n = 65) and high NAL (NAL+, n = 35) assessed via PET, and further stratified into subjective memory complainers (SMC; nNAL- = 51, nNAL+ = 25) and non-SMC (nNAL- = 14, nNAL+ = 10) based on the Memory Assessment Clinic- Questionnaire. Plasma NFL inversely correlated with cognitive performance. No significant difference in NFL was observed between NAL+ and NAL- participants; however, within APOEɛ4 non-carriers, higher NAL was observed in individuals with NFL concentrations within quartiles 3 and 4 (versus quartile 1). Additionally, within the NAL+ participants, SMC had a trend of higher NFL compared to non-SMC. Plasma NFL is inversely associated with cognitive performance in elderly individuals. While plasma NFL may not reflect NAL in individuals with normal global cognition, the current observations indicate that onset of axonal injury, reflected by increased plasma NFL, within the preclinical phase of AD may contribute to the pathogenesis of AD.

1. Neural recordings were made from motor fascicles of the ulnar or radial nerves while the motor cortex was stimulated percutaneously using high-voltage electrical stimuli or transient magnetic pulses to determine whether human muscle spindle endings could be activated by such stimuli and, if so, whether this occurred before the recruitment of alpha-motoneurones. 2. In relaxed subjects, no evidence of muscle spindle activation could be detected in nine recordings of multiunit neural activity and four recordings from single spindle afferents using stimulus levels up to 600 V and 1.5 T. These levels produced a prominent twitch contraction of the intrinsic muscles of the hand and of forearm muscles. Passive stretch of the contracting muscle did not reveal a fusimotor action too weak to be detected under isometric circumstances. 3. With twenty-six single spindle afferents, the stimuli were delivered during a voluntary contraction of the receptor-bearing muscle. This served to 'focus' the effects of the stimulus on the relevant motoneurone pools and increased the probability that fusimotor neurones innervating the endings were active. 4. None of the twenty-six spindle afferents could be activated by stimuli subthreshold for alpha-motoneurones, even when the stimuli were delivered during passive stretch of the contracting muscle. With eighteen afferents, stimuli above threshold for alpha-motoneurones were delivered: twelve remained unaffected but the discharge of six altered. 5. Three afferents were activated at latencies of 35, 39 and 40 ms, respectively 16, 20 and 20 ms after the onset of the EMG potentials in the receptor-bearing muscles. This latency difference is too short to be attributable to activation of gamma-motoneurones: arguments are presented that the increase in spindle discharge could result from activation of beta-motoneurones. 6. The discharge of three afferents increased at latencies of 70, 75 and 85 ms, too early to be due to stretch on the falling phase of the twitch contraction of the receptor-bearing muscle. Responses at these latencies could involve activation of gamma- or beta-motoneurones. 7. These findings in human subjects suggest that transient stimulation of the motor cortex may effectively access fusimotor neurones.