Michal Schnaider Beeri’s research while affiliated with Rutgers New Jersey Medical School and other places

INTRODUCTION We developed a tool for objective quantification of apathy. METHODS Participants (n = 97; 67 with cognitive impairment, 30 cognitively normal; mean age = 74.3 ± 6.2 years, 56.7% females) were exposed to emotional and cognitive stimuli in a virtual reality environment. Gaze metrics (time to first fixation [TTFF] and total fixation duration [TFD]) and autonomic nervous system (ANS) reactivity were measured. Apathy and depression were clinically assessed using the Lille Apathy Rating Scale short version and the Geriatric Depression Scale 15‐item version, respectively. Cutoffs of ≥ –7 and ≥ 5 were used to define apathy and depression, respectively. RESULTS The sample comprised 14 participants with apathy only, 9 with depression only, 10 with both, 63 with neither, and 1 with missing data. For all emotional stimuli, participants with apathy only showed longer TTFF (P = 0.039, effect sizes [ES] = 0.798), and shorter TFD (P = 0.023, ES = 0.578) compared to those without apathy or depression. ANS reactivity was not associated with apathy. DISCUSSION Apathy is associated with decreased gaze engagement at emotional stimuli. Highlights Apathy measurement via questionnaires is limited by subjectivity biases. Apathy measurement via questionnaires is limited by simplistic scoring. We present a novel method for objective measurement of apathy. Gaze characteristics reflect the emotional and cognitive components of apathy.

INTRODUCTION Associations between amyloid‐tau‐neurodegeneration (ATN) plasma biomarkers and cognition have not been characterized in adults with type 1 diabetes (T1D). METHODS Using data from participants in the Glycemic Variability and Fluctuations in Cognitive Status in Adults with T1D (GluCog) study (N = 114), we evaluated associations between phosphorylated tau (pTau)181, pTau217, β‐amyloid 42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) and self‐administered digital cognitive tests, adjusting for age, sex, education, comorbidities (e.g., kidney disease), and glycemic indices. RESULTS Higher concentrations of pTau181 and GFAP were associated with slower responses on working memory tasks (pTau181: β = 0.261; p = 0.007; GFAP: β = 0.175, p = 0.036), and higher β‐amyloid 42/40 ratio was associated with better vocabulary (β = 0.260, p = 0.009). Discussion Digital cognitive performance was associated with several ATN plasma biomarkers in T1D adults. Prospective studies are needed to understand the utility of these biomarkers in T1D. Highlights There is an increase in life expectancy for individuals with type 1 diabetes (T1D). Few studies investigate the relationship between T1D and neurodegeneration. We characterize the relation between ATN plasma biomarkers and cognitive function. Digital cognitive performance was associated with plasma biomarkers in T1D adults.

Adults with prediabetes are at risk for Alzheimer's Disease and Related Dementia (ADRD). While exercise may lower ADRD risk, the exact mechanism is unclear. We tested the hypothesis that short‐term exercise would raise neuronal insulin signaling and pro‐BDNF in neuronal extracellular vesicles (nEVs) in prediabetes. Twenty‐one older adults (18F, 60.0 ± 8.6 yrs.; BMI: 33.5 ± 1.1 kg/m²) with prediabetes (ADA criteria; 75 g OGTT) were randomized to 12 supervised work‐matched continuous (n = 13, 70% HRpeak) or interval (n = 8, 90% HRpeak and 50% HRpeak for 3 min each) sessions over 2‐wks for 60 min/d. Aerobic fitness (VO2peak) and body weight were assessed. After an overnight fast, whole‐body glucose tolerance (total area under the curve, tAUC) and insulin sensitivity (SIis) were determined from a 120 min 75 g OGTT. nEVs were acquired from 0 and 60 min time‐points of the OGTT, and levels of insulin signaling proteins (i.e., p‐IRS‐1, total−/p‐Akt, pERK1/2, pJNK1/2, and pp38) and pro‐BNDF were measured. OGTT stimulatory effects were calculated from protein differences (i.e., OGTT 60‐0 min). Adults were collapsed into a single group as exercise intensity did not affect nEV outcomes. Exercise raised VO2peak (+1.4 ± 2.0 mL/kg/min, p = 0.008) and insulin sensitivity (p = 0.01) as well as decreased weight (−0.4 ± 0.9 kg, p = 0.04) and whole‐body glucose tAUC120min (p = 0.02). Training lowered 0‐min pro‐BDNF (704.1 ± 1019.0 vs. 414.5 ± 533.5, p = 0.04) and increased OGTT‐stimulated tAkt (−51.8 ± 147.2 vs. 95 ± 204.5 a.u., p = 0.01), which was paralleled by reduced pAkt/tAkt at 60 min of the OGTT (1.3 ± 0.2 vs. 1.2 ± 0.1 a.u., p = 0.04). Thus, 2 weeks of exercise altered neuronal insulin signaling responses to glucose ingestion and lowered pro‐BNDF among adults with prediabetes, thereby potentially lowering ADRD risk.

The Rey Auditory Verbal Learning Test (RAVLT) is a commonly used tool for evaluating verbal learning and memory in neuropsychological assessments. In recent years, we developed a Virtual Reality (VR) adaptation of the RAVLT (VR-RVLT), aiming for increased ecological validity compared to the traditional pen and paper gold standard (GS-RAVLT). Following validation in healthy cohorts, the VR-RAVLT was validated with thirty individuals with Parkinson's Disease (PD) that completed both the GS-RAVLT and the VR- RAVLT. Validity of the VR-RAVLT was evaluated by assessing its construct and discriminant validity, and test–retest reliability, in comparison to the GS-RAVLT. Results of the PD participants were compared to those of 46 previously recruited healthy participants with comparable age and level of education. Main outcome measures derived from the remembered items on the test lists, exhibited significant and comparable correlations between VR-RAVLT and GS-RAVLT, both among healthy participants and PD participants. Likewise, serial position effects were similar for both formats amog the PD participants. Additionally, both formats showed similar discriminatory ability between healthy controls and PD participants, as well as comparable test–retest reliability measures. Taken together, the results suggest that the VR-based RAVLT is equally effective in measuring verbal memory capabilities in individuals with PD as compared to the GS-RAVLT. Certain results indicate that the virtual reality version has the capability to encompass additional factors that might impact memory performance, thereby suggesting an enhanced ecological validity.

Introduction Depression and its components significantly impact dementia prediction and severity, necessitating reliable objective measures for quantification. Methods We investigated associations between emotion‐based speech measures (valence, arousal, and dominance) during picture descriptions and depression dimensions derived from the geriatric depression scale (GDS, dysphoria, withdrawal‐apathy‐vigor (WAV), anxiety, hopelessness, and subjective memory complaint). Results Higher WAV was associated with more negative valence (estimate = ‐0.133, p = 0.030). While interactions of apolipoprotein E (APOE) 4 status with depression dimensions on emotional valence did not reach significance, there was a trend for more negative valence with higher dysphoria in those with at least one APOE4 allele (estimate = –0.404, p = 0.0846). Associations were similar irrespective of dementia severity. Discussion Our study underscores the potential utility of speech biomarkers in characterizing depression dimensions. In future research, using emotionally charged stimuli may enhance emotional measure elicitation. The role of APOE on the interaction of speech markers and depression dimensions warrants further exploration with greater sample sizes. Highlights Participants reporting higher apathy used more negative words to describe a neutral picture. Those with higher dysphoria and at least one APOE4 allele also tended to use more negative words. Our results suggest the potential use of speech biomarkers in characterizing depression dimensions.

Introduction & Objective: Prediabetes raises Alzheimer’s Disease and Related Dementia (ADRD) risk. While exercise may lower ADRD risk, it is unclear if it does so by raising brain insulin sensitivity and/or brain derived neurotrophic growth factor (BDNF). We hypothesized that short-term exercise would raise brain insulin signaling and BDNF from neuronal extracellular vesicles (nEVs) in adults with prediabetes. Methods: Twenty-one adults (18F, 60.0±8.6 y; 33.5±1.1 kg/m2) with prediabetes (75g OGTT, ADA criteria) were randomized to 12 supervised work-matched continuous (n=13, 70% HRpeak) or interval (n=8, 90% and 50% HRpeak for 3 min each) sessions over 2-wks for 60 min/d. Aerobic fitness (VO2peak) and body weight were assessed. After an overnight fast, whole-body glucose tolerance (total area under the curve, tAUC) and insulin resistance (glucose x insulin tAUC) were determined from a 120min 75g OGTT. nEVs were measured at 0- and 60min of the OGTT to depict phosphorylated insulin signaling (i.e. p-IRS-1, total/pAkt, pERK1/2, pJNK1/2 and pp38) and pro-BNDF. OGTT stimulated effects were calculated from protein differences (i.e. 60-0min). Results: Adults were collapsed into a single group as exercise intensity did not affect measures. Exercise raised VO2peak (+1.4±2.0 ml/kg/min, P<0.01) and decreased weight (-0.4±0.9 kg, P=0.04) as well as whole-body glucose tAUC120min (P=0.02) and insulin resistance (P=0.01). Training lowered fasting pro-BDNF (704.1±1019.0 vs. 414.5±533.5 pg/ml, P=0.04), and increased OGTT-stimulated tAkt (-51.8±147.2 vs. 95±204.5 a.u., P=0.01), which was paralleled by reduced pAkt/total-Akt at 60min of the OGTT (1.3±0.2 vs. 1.2±0.1 a.u., P=0.04). No other insulin protein was impacted by exercise. Conclusion: Two weeks of exercise altered brain insulin signaling responses to the OGTT and lowered pro-BNDF in adults with prediabetes. Further work is needed to assess if exercise-induced brain insulin sensitivity contributes to ADRD risk reduction. Disclosure S.K. Malin: None. D.J. Battillo: None. B.A. Chaudhry: None. M.S. Beeri: None. F. Delgado-Peraza: None. D. Kapogiannis: None. Funding National Institutes of Health (RO1-HL130296)

Background and objectives: Molecular omics studies have identified proteins related to cognitive resilience but unrelated to Alzheimer disease and Alzheimer disease-related dementia (AD/ADRD) pathologies. Posttranslational modifications of proteins with glycans can modify protein function. In this study, we identified glycopeptiforms associated with cognitive resilience. Methods: We studied brains from adults with annual cognitive testing with postmortem indices of 10 AD/ADRD pathologies and proteome-wide data from dorsal lateral prefrontal cortex (DLPFC). We quantified 11, 012 glycopeptiforms from DLPFC using liquid chromatography with tandem mass spectrometry. We used linear mixed-effects models to identify glycopeptiforms associated with cognitive decline correcting for multiple comparisons (p < 5 × 10-6). Then, we regressed out the effect of AD/ADRD pathologies to identify glycopeptiforms that may provide cognitive resilience. Results: We studied 366 brains, average age at death 89 years, and 70% female with no cognitive impairment = 152, mild cognitive impairment = 93, and AD = 121 cognitive status at death. In models adjusting for age, sex and education, 11 glycopeptiforms were associated with cognitive decline. In further modeling, 8 of these glycopeptiforms remained associated with cognitive decline after adjusting for AD/ADRD pathologies: NPTX2a (Est., 0.030, SE, 0.005, p = 1 × 10-4); NPTX2b (Est.,0.019, SE, 0.005, p = 2 × 10-4) NECTIN1(Est., 0.029, SE, 0.009, p = 9 × 10-4), NPTX2c (Est., 0.015, SE, 0.004, p = 9 × 10-4), HSPB1 (Est., -0.021, SE, 0.006, p = 2 × 10-4), PLTP (Est., -0.027, SE, 0.009, p = 4.2 × 10-3), NAGK (Est., -0.027, SE, 0.008, p = 1.4 × 10-3), and VAT1 (Est., -0.020, SE, 0.006, p = 1.1 × 10-3). Higher levels of 4 resilience glycopeptiforms derived through glycosylation were associated with slower decline and higher levels of 4 derived through glycation were related to faster decline. Together, these 8 glycopeptiforms accounted for an additional 6% of cognitive decline over the 33% accounted for the 10 brain pathologies and demographics. All 8 resilience glycopeptiforms remained associated with cognitive decline after adjustments for the expression level of their corresponding protein. Exploratory gene ontology suggested that molecular mechanisms of glycopeptiforms associated with cognitive decline may involve metabolic pathways including pyruvate and NADH pathways and highlighted the importance of molecular mechanisms involved in glucose metabolism. Discussion: Glycopeptiforms in aging brains may provide cognitive resilience. Targeting these glycopeptiforms may lead to therapies that maintain cognition through resilience.

Objective High BMI, which poorly represents specific fat depots, is linked to poorer cognition and higher dementia risk, with different associations between sexes. This study examined associations of abdominal fat depots with cognition and brain volumes and whether sex modifies this association. Methods A total of 204 healthy middle‐aged offspring of Alzheimer's dementia patients (mean age = 59.44, 60% females) underwent abdominal magnetic resonance imaging to quantify hepatic, pancreatic, visceral, and subcutaneous adipose tissue and to assess cognition and brain volumes. Results In the whole sample, higher hepatic fat percentage was associated with lower total gray matter volume ( β = −0.17, p < 0.01). Primarily in males, higher pancreatic fat percentage was associated with lower global cognition (males: β = −0.27, p = 0.03; females: β = 0.01, p = 0.93) executive function (males: β = −0.27, p = 0.03; females: β = 0.02, p = 0.87), episodic memory (males: β = −0.28, p = 0.03; females: β = 0.07, p = 0.48), and inferior frontal gyrus volume (males: β = −0.28, p = 0.02; females: β = 0.10, p = 0.33). Visceral and subcutaneous adipose tissue was inversely associated with middle frontal and superior frontal gyrus volumes in males and females. Conclusions In middle‐aged males at high Alzheimer's dementia risk, but not in females, higher pancreatic fat was associated with lower cognition and brain volumes. These findings suggest a potential sex‐specific link between distinct abdominal fat with brain health.

Background: The efficacy of vitamin E in prevention of diabetes-related complications differs by Haptoglobin (Hp) genotype. Objective: To examine the role of Hp genotype in the relationship of vitamin E intake with brain volume in cognitively normal elderly patients with type 2 diabetes. Methods: Brain volumes for the superior, middle, and inferior frontal gyri and for the middle temporal gyrus were generated from structural T1 MRI in 181 study participants (Hp 1-1: n = 24, Hp 2-1: n = 77, Hp 2-2: n = 80). Daily vitamin E intake was assessed using the Food Frequency Questionnaire. Analyses of covariance, controlling for demographic and cardiovascular variables was used to evaluate whether the association of daily vitamin E intake with brain volume was modified by Hp genotype. Results: Average age was 70.8 (SD = 4.2) with 40% females, and mean Mini-Mental State Examination score of 28.17 (SD = 1.90). A significant interaction was found between vitamin E intake and Hp genotype in inferior frontal gyrus’ volume; p = 0.0108. For every 1 microgram increase in vitamin E intake, the volume of the inferior frontal gyrus decreased by 0.955% for Hp 1-1 (p = 0.0348), increased by 0.429% for Hp 2-1 (p = 0.0457), and by 0.077% for Hp 2-2 (p = 0.6318). There were no significant interactions between vitamin E intake and Hp genotype for the middle (p = 0.6011) and superior (p = 0.2025) frontal gyri or for the middle temporal gyrus (p = 0.503). Conclusions: The effect of dietary vitamin E on the brain may differ by Hp genotype. Studies examining the impact of vitamin E on brain-related outcomes should consider Hp genotype.