Gloria Benson

Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline

Supplementation of spermidine, an autophagy-inducing agent, has been shown to protect against neurodegeneration and cognitive decline in aged animal models. The present translational study aimed to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations. In a preclinical toxicity study, supplementation of spermidine using this extract did not result in morbidities or changes in behavior in BALBc/Rj mice during the 28-days repeated-dose tolerance study. Post mortem examination of the mice organs showed no increase in tumorigenic and fibrotic events. In the human cohort (participants with subjective cognitive decline, n=30, 60 to 80 years of age), a 3-month randomized, placebo-controlled, double-blind Phase II trial was conducted with supplementation of the spermidine-rich plant extract (dosage: 1.2 mg/day). No differences were observed between spermidine and placebo-treated groups in vital signs, weight, clinical chemistry and hematological parameters of safety, as well as in self-reported health status at the end of intervention. Compliance rates above 85% indicated excellent tolerability. The data demonstrate that spermidine supplementation using a spermidine-rich plant extract is safe and well-tolerated in mice and older adults. These findings allow for longer-term intervention studies in humans to investigate the impact of spermidine treatment on cognition and brain integrity.

Individual Correspondence of Amyloid-β and Intrinsic Connectivity in the Posterior Default Mode Network Across Stages of Alzheimer’s Disease

In Alzheimers disease (AD), amyloid-β (Aβ) pathology and intrinsic functional connectivity (iFC) interact. Across stages of AD, we expected individual spatial correspondence of Aβ and iFC to reveal both Aβ accumulation and its detrimental effects on iFC. We used resting-state functional magnetic imaging and Aβ imaging in a cross-sectional sample of 90 subjects across stages of AD and healthy older adults. Global and local correspondence of Aβ and iFC were assessed within the posterior default mode network (pDMN) by within-subject voxel-wise correlations. Beginning at preclinical stages, global Aβ-iFC correspondence was positive for the whole pDMN, showing that Aβ accumulates in areas of high connectivity, and reached a plateau at prodromal stages. Starting at preclinical stages, local correspondence was negative in network centers, indicating that Aβ reduces connectivity of the pDMN as a function of local plaque concentration, and peaked at prodromal stages. Positive global correspondence suggests that Aβ accumulation progresses along iFC, with this effect starting in preclinical stages, and being constant along clinical periods. Negative local correspondence suggests detrimental effects of Aβ on iFC in network centers, starting at preclinical stages, and peaking when first symptoms appear. Data reveal a complex trajectory of Aβ and iFC correspondence, affecting both Aβ accumulation and iFC impairments.

Performance of Spanish-speaking community-dwelling elders in the United States on the Uniform Data Set

Spanish is the second‐most common language spoken in the United States, and Spanish speakers represent one third of the aging population. The National Alzheimers Coordinating Centers Uniform Data Set implemented a Spanish neuropsychological battery. Previous work described the neuropsychological performance for English speakers. Here we describe performance on the Spanish version.

BEYOND ANXIETY AND DEPRESSION: RUMINATION, STRESS COPING, AND QUALITY OF LIFE IN SUBJECTIVE COGNITIVE DECLINE

Background: Subjective cognitive decline (SCD) is consistently associated with adverse affects, such as subclinical depression, anxiety, along with poor psychological well-being. However, detailed aspects of psychological stress, a potential predictor of brain alteration and cognitive decline, have rarely been studied in this group. We aimed to further characterize the affective profile of SCD by assessing rumination, stress coping, and psychological quality of life in this at-risk cohort. Methods: In total 60 individuals, 30 SCDs (70.665.4 years) and 30 healthy older adults (HO) (70.767.3), underwent cognitive evaluation and filled out self-reported questionnaires. We examined associations of global cognitive complaints (Every Day Cognition, ECog), global cognition (neuropsychological composite), cognitive response styles of rumination and distraction (Response Style Questionnaire RSQ), negative and positive stress coping (Stress Coping Questionnaire SVF-78), and quality of life (WHO Quality of Life WHoQol). Correlation and mediation analyses were conducted to highlight relationships between cognitive and affective variables. Results: In the total sample, cognitive complaints were significantly associated with higher symptom rumination, negative coping, and lower quality of life in the psychological domain (Table 1); with SCD reporting higher symptom rumination and lower quality of life when compared to HO. Mediation models corroborated a significant indirect effect of cognitive complaints on quality of life through symptom rumination (b1⁄4-5.9, CI: -13.06, -1.17) Similar relationships were not found for global cognition in the total sample. However, in the SCD group, lower global cognition was associated with negative coping strategies(r1⁄4-.40). Additionally, negative coping mediated the adverse impact of lower cognition on psychological well-being (b1⁄45.03 CI: .08, .75). Conclusions:Our findings suggest that symptom rumination and negative stress coping help form the psychological profile of SCD. In addition, these factors play a central role on how complaints and cognition compromise psychological well-being. Rumination and stress are associated with cognitive debt [1], which may increase the vulnerability of the brain and cognitive function to pathological changes. Interventions that target these specific affective factors may increase quality of life and reduce risk of future

SPERMIDINE SUPPLEMENTATION TO IMPROVE EPISODIC MEMORY IN AGING ADULTS AT RISK OF DEMENTIA

BI 409306 (10–50 mg) or placebo daily for 12 weeks. The primary endpoint was the change from baseline atWeek 12 in the Neuropsychological Test Battery total score. Secondary endpoints included the change from baseline at Week 12 in the Clinical Dementia Rating – Sum of Boxes (CDR-SB) and the AD Assessment Scalecognitive subscale (ADAS-Cog11) total score. AD Cooperative Study/Activities of Daily Living (ADCS-ADL) for mild cognitive impairment (ADCS-MCI-ADL) in Study 1, and ADCS-ADL in Study 2 were also assessed as secondary endpoints. Data from both studies were pooled, and analyzed using mixed model repeated measurement. Adverse events (AEs) were recorded. Results:Overall, 457 patients were randomized. The results obtained from the pooled analysis gave no indication of a treatment benefit for BI 409306 compared with placebo, with similar findings observed for the individual studies. BI 409306 was generally well tolerated. The highest frequency of AEs occurred in the BI 409306 50-mg dose group. Safety findings for the individual studies were also consistent with those from the pooled analysis. Conclusions: No clinically meaningful changes from baseline were observed across a range of BI 409306 doses administered to patients with prodromal or mild AD. Funding: Boehringer Ingelheim.

GLOBAL AND LOCAL INTERACTIONS BETWEEN AMYLOID-B PATHOLOGY AND INTRINSIC CONNECTIVITY ALONG THE SPECTRUM OF ALZHEIMER’S DISEASE

AV1451, we generated SUVR images for the interval between 80-100 minutes post-injection, and used the mean SUVR values from 4mm spheres drawn around the peak voxels as independent variables in whole-brain voxelwise covariance analyses of [F] AV1451 uptake (p<0.05 FWE corrected, no covariates). For resting-state fMRI data, we used the peak voxels as seeds to extract intrinsic connectivity maps.We then performed visual inspection of the covariance and functional connectivity maps to assess their overlap, and goodness-of-fit analyses for [F]AV1451 covariance maps against 8 predefined functional network templates. Results: There was a striking overlap between [F]AV1451 covariance and intrinsic connectivity maps (Figure 1). Goodness-of-fit showed strongest overlap between rMOG and the higher visual network, lSTG and the language network, rMFG and the executive control network, and lPCC with the posterior default mode network (Table 2). Conclusions:The spatial pattern of tau observed in AD patients does resemble the functional organization of the healthy brain, supporting the notion that tau pathology spreads through circumscribed brain networks.

Self and proxy ratings of patient-reported outcomes: Impact of cognitive status

Jefferson’s sample, which were highly educated white participants already enrolled in longitudinal research. No significant differences were found between the two groups regarding allocation of resources for research and attitudes towards positive outcomes of medical research, indicating a generally favorable attitude towards research. Our results highlight the importance of developing educational and social opportunities that foster relationships, decrease mistrust and address safety concerns.