Tripartite Relationship Among Synaptic, Amyloid, and Tau Proteins: An In Vivo and Postmortem Study.

OBJECTIVE: To test the hypothesis that fundamental relationships along the amyloid, tau, and neurodegeneration (A/T/N) cascade depend on synaptic integrity in older adults in-vivo and postmortem. METHODS: Two independent observational, cross-sectional cohorts: 1) in-vivo community-dwelling, clinically normal adults from the UCSF Memory and Aging Center completed lumbar puncture and MRI (exclusion criteria, CDR>0), and 2) postmortem decedents from the Rush Memory and Aging Project (exclusion criteria, inability to sign informed consent). In-vivo measures included cerebrospinal fluid (CSF) synaptic proteins (synaptotagmin-1, SNAP-25, neurogranin, and GAP-43), Aß42/40, ptau181, and MRI gray matter volume (GMV). Postmortem measures captured brain tissue levels of presynaptic proteins (complexin-I, complexin-II, VAMP, and SNARE complex), and neuritic plaque and neurofibrillary tangle (NFT) counts. Regression models tested statistical moderation of synaptic protein levels along the A/T/N cascade (synaptic proteins*amyloid on tau, and synaptic proteins*tau on GMV). RESULTS: 68 in-vivo older adults (age=71y, 43%F) and 633 decedents (age=90y, 68%F, 34% clinically normal) were included. Each in-vivo CSF synaptic protein moderated the relationship between Aß42/40 and ptau181 (-0.23<𝛽s<-0.12, ps<0.05) and the relationship between ptau and GMV (-0.49<𝛽s<-0.32, ps<0.05). Individuals with more abnormal CSF synaptic protein demonstrated expected relationships between Aß-ptau and ptau-brain volume, effects that were absent or reversed in those with more normal CSF synaptic protein. Postmortem analyses recapitulated CSF models. More normal brain tissue levels of complexin-I, VAMP, and SNARE moderated the adverse relationship between neuritic plaque and NFT counts (-0.10<𝛽s<-0.08, ps<0.05). CONCLUSIONS: Pathogenic relationships of Aß and tau may depend on synaptic state. Synaptic markers may help identify risk and/or resilience to AD proteinopathy.

The role of executive functioning in memory performance in pediatric focal epilepsy.

OBJECTIVE: Learning and memory are essential for academic success and everyday functioning, but the pattern of memory skills and its relationship to executive functioning in children with focal epilepsy is not fully delineated. We address a gap in the literature by examining the relationship between memory and executive functioning in a pediatric focal epilepsy population. METHODS: Seventy children with focal epilepsy and 70 typically developing children matched on age, intellectual functioning, and gender underwent neuropsychological assessment, including measures of intelligence (Wechsler Abbreviated Scale of Intelligence [WASI]/Differential Ability Scales [DAS]), as well as visual Children's Memory Scale (CMS Dot Locations) and verbal episodic memory (Wide Range Assessment of Memory and Learning [WRAML] Story Memory and California Verbal Learning Test for Children [CVLT-C]). Executive functioning was measured directly (WISC-IV Digit Span Backward; Clinical Evaluation of Language Fundamentals, Fourth Edition (CELF-IV) Recalling Sentences) and by parent report (Behavior Rating Inventory of Executive Function [BRIEF]). RESULTS: Children with focal epilepsy had lower delayed free-recall scores than controls across visual and verbal memory tasks (p = 0.02; partial η2 = 0.12). In contrast, recognition memory performance was similar for patients and controls (p = 0.36; partial η2 = 0.03). Children with focal epilepsy demonstrated difficulties in working memory (p = 0.02; partial η2 = 0.08) and planning/organization (p = 0.02) compared to controls. Working memory predicted 9-19% of the variance in delayed free recall for verbal and visual memory; organization predicted 9-10% of the variance in verbal memory. Patients with both left and right focal epilepsy demonstrated more difficulty on verbal versus visual tasks (p = 0.002). Memory performance did not differ by location of seizure foci (temporal vs. extratemporal, frontal vs. extrafrontal). SIGNIFICANCE: Children with focal epilepsy demonstrated memory ability within age-level expectations, but delayed free recall was inefficient compared to typically developing controls. Memory difficulties were not related to general cognitive impairment or seizure localization. Executive functioning accounted for significant variance in memory performance, suggesting that poor executive control negatively influences memory retrieval.

Self-predictions of prospective memory in HIV-associated neurocognitive disorders: evidence of a metamemory deficit.

HIV-associated neurocognitive disorders (HAND) are associated with deficits in prospective memory (PM; "remembering to remember"), conferring risk of daily functioning declines. However, self-perceptions of PM functioning are not reliably associated with PM performance in HIV, suggesting a possible deficit in awareness of PM abilities (meta-PM). Our study examined meta-PM in HAND and its correlates using self-predictions of laboratory-based PM performance. Performance-based PM abilities, self-reported prediction of PM performance, and PM complaints in everyday life were assessed in 49 individuals with HAND, 93 HIV+ without HAND (HIV+ noHAND), and 121 seronegative adults (HIV-). After controlling for group-level differences, HAND was associated with a greater number of PM symptoms in everyday life and worse PM performance when compared with both HIV+ noHAND and HIV- samples. Although HAND individuals reported somewhat lower predictions regarding their laboratory PM performance relative to the other study groups, they nevertheless exhibited significantly greater inaccurate overconfidence in time-based PM abilities. Within the HAND group, overconfidence in time-based meta-PM was associated with executive dysfunction and antiretroviral (ARV) nonadherence. HAND individuals evidenced a moderate deficit in awareness of PM functioning characterized by overconfidence in time-based PM abilities. Overconfidence in PM may result in absence of compensatory strategy use, and lead to increased errors in daily functioning (e.g., ARV nonadherence).