DRD4 genotype predicts longevity in mouse and human

Longevity is influenced by genetic and environmental factors. The brain's dopamine system may be particularly relevant, since it modulates traits (e.g., sensitivity to reward, incentive motivation, sustained effort) that impact behavioral responses to the environment. In particular, the dopamine D4 receptor (DRD4) has been shown to moderate the impact of environments on behavior and health. We tested the hypothesis that the DRD4 gene influences longevity and that its impact is mediated through environmental effects. Surviving participants of a 30-year-old population-based health survey (N = 310; age range, 90-109 years; the 90+ Study) were genotyped/resequenced at the DRD4 gene and compared with a European ancestry-matched younger population (N = 2902; age range, 7-45 years). We found that the oldest-old population had a 66% increase in individuals carrying the DRD4 7R allele relative to the younger sample (p = 3.5 × 10(-9)), and that this genotype was strongly correlated with increased levels of physical activity. Consistent with these results, DRD4 knock-out mice, when compared with wild-type and heterozygous mice, displayed a 7-9.7% decrease in lifespan, reduced spontaneous locomotor activity, and no lifespan increase when reared in an enriched environment. These results support the hypothesis that DRD4 gene variants contribute to longevity in humans and in mice, and suggest that this effect is mediated by shaping behavioral responses to the environment.Fil: Grady, Deborah L.. University of California. College of Medicine. Department of Biological Chemistry; Estados UnidosFil: Thanos, Panayotis K.. National Institute on Alcohol Abuse and Alcoholism. Laboratory of Neuroimaging; Estados Unidos. Brookhaven National Laboratory. Medical Department. Behavioral Neuropharmocology and Neuroimaging Laboratory; Estados Unidos. Stony Brook University. Department of Psychology; Estados UnidosFil: Corrada, Maria M.. University of California. Department of Neurology; Estados UnidosFil: Barnett Jr., Jeffrey C.. Brookhaven National Laboratory. Medical Department. Behavioral Neuropharmocology and Neuroimaging Laboratory; Estados UnidosFil: Ciobanu, Valentina. University of California. College of Medicine. Department of Biological Chemistry; Estados UnidosFil: Shustarovich, Diana. Brookhaven National Laboratory. Medical Department. Behavioral Neuropharmocology and Neuroimaging Laboratory; Estados UnidosFil: Napoli, Anthony. Brookhaven National Laboratory. Medical Department. Behavioral Neuropharmocology and Neuroimaging Laboratory; Estados UnidosFil: Moyzis, Alexandra G.. University of California. College of Medicine. Department of Biological Chemistry; Estados UnidosFil: Grandy, David. Oregon Health Sciences University. Physiology and Pharmacology; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; ArgentinaFil: Wang, Gene-Jack. Brookhaven National Laboratory. Medical Department. Behavioral Neuropharmocology and Neuroimaging Laboratory; Estados UnidosFil: Kawas, Claudia H.. University of California. Department of Neurology; Estados UnidosFil: Chen, Chuansheng. University of California. Department of Psychology and Social Behavior; Estados UnidosFil: Dong, Qi. Beijing Normal University. National Key Laboratory of Cognitive Neuroscience and Learning; ChinaFil: Wang, Eric. University of California. College of Medicine. Department of Biological Chemistry; Estados Unidos. Aria Diagnostics Inc.; Estados Unidos. University of California. Institute of Genomics and Bioinformatics; Estados UnidosFil: Volkow, Nora D.. National Institute on Alcohol Abuse and Alcoholism. Laboratory of Neuroimaging; Estados Unidos. Brookhaven National Laboratory. Medical Department. Behavioral Neuropharmocology and Neuroimaging Laboratory; Estados Unidos. National Institute on Drug Abuse; Estados UnidosFil: Moyzis, Robert K.. University of California. College of Medicine. Department of Biological Chemistry; Estados Unidos. Beijing Normal University. National Key Laboratory of Cognitive Neuroscience and Learning; China. University of California. Institute of Genomics and Bioinformatics; Estados Unido

In Situ Labeling of Dying Cortical Neurons in Normal Aging and in Alzheimer's Disease: Correlations with Senile Plaques and Disease Progression

We examined the degeneration of neocortical neurons in normal aging and Alzheimer's disease (AD) using terminal transferase (TdT)-mediated deoxyuridine triphosphate (d-UTP)-biotin nick-end labeling (TUNEL), a method that identifies DNA strand breaks and constitutes a positive marker for dying neurons. TUNEL was positive in neurons, glia, and microglial cells in AD but not in younger or age-matched cognitively characterized controls. Neuronal labeling in AD was most conspicuous in cortical layer III in the early stages of the disease and became more widespread as the disease progressed. In addition, we observed TUNEL of lamina III neurons in a subset of older subjects who had normal cognition but abundant neocortical senile plaques. In concert, the availability of a direct marker of dying neurons allows for specific correlations of cell death with other neuropathological markers as well as clinical variables. Observations from the present study suggest that the death of cortical neurons precedes the symptomatic stage of AD and evolves in parallel with the clinical progression of the disease and that there appears to be an association between the degree of cell death and the severity of senile plaques

Shape-Optimized Electrooptic Beam Scanners: Experiment

A new horn-shaped electrooptic scanner is described with significantly improved scanning sensitivity over rectangular-shaped devices. In the new device, the shape of the scanner is chosen to follow the trajectory of the beam. An example design is described that exhibits a factor of two larger scanning sensitivity than a rectangular device with comparable maximum scanning angle. Beam propagation simulations and measurements on an experimental device verify the scanner performance.Comment: 3 pages, 3 figures. IEEE Photonics Technology Letters. Author Jennifer C. Fang is currently known as Jennifer Andreoli-Fan

Monitoring carbon dioxide concentration for early detection of spoilage in stored grain

Field experiments were conducted in storage silos to evaluate carbon dioxide sensors to monitor spoilage in grain prior to spoilage detection by traditional methods such as visual inspections and temperature cables. Carbon dioxide concentrations in the storage silo were monitored up to eight months and correlated to the presence of stored-product insects, molds and mycotoxin levels in the stored grain. The data showed that safe grain storage was observed at CO2 concentrations of 400 to 500 ppm. Higher concentrations of CO2 clearly showed mold spoilage or insect activity inside the grain storage silo. Carbon dioxide concentrations of 500 to 1200 ppm indicated onset of mold infection where as CO2 concentrations of 1500 to 4000 ppm and beyond clearly indicated severe mold infection or stored-product insects infestation. The percent kernel infection was in the range of 30% for CO2 concentrations of 500 to 1000 ppm to 90% for CO2 concentrations of 9000 ppm. Fungal concentrations were in the range of 2.0 ×102 colony forming units per gram (cfu/g) at 500 ppm CO2 concentration to 6.5 ×107 cfu/g at 9000 ppm CO2 concentration. Fungi of genera Aspergillus spp., Penicillium spp., and Fusarium spp. were isolated from spoiled grain. High concentration of fungi and presence of mycotoxins (aflatoxin: 2 ppb and Deoxynivalenol (DON): 1 ppm) were correlated with high CO2 concentration in the silos. The findings from this research will be helpful in providing more timely information regarding safe storage limits, aeration requirements and costs of spoilage mitigation measures such as turning, aerating and fumigating grain. Additionally, it will provide information on preventive stored grain quality management practices that should reduce residue levels of mycotoxins, pesticides and other foreign material in our food supply. The CO2 monitoring technology will increase the quality and quantity of stored grain, while saving the U.S. and global grain production, handling and processing industry millions of dollars annually. Keywords: Carbon dioxide, Grain storage, Stored-product insects, Mold and mycotoxi

How VEGF-A and its splice variants affect breast cancer development – clinical implications

Background: Altered expression levels and structural variations in the vascular endothelial growth factor (VEGF) have been found to play important roles in cancer development and to be associated with the overall survival and therapy response of cancer patients. Particularly VEGF-A and its splice variants have been found to affect physiological and pathological angiogenic processes, including tumor angiogenesis, correlating with tumor progression, mostly caused by overexpression. This review focuses on the expression and impact of VEGF-A splice variants under physiologic conditions and in tumors and, in particular, the distribution and role of isoform VEGF(165)b in breast cancer. Conclusions and perspectives: Many publications already highlighted the importance of VEGF-A and its splice variants in tumor therapy, especially in breast cancer, which are summarized in this review. Furthermore, we were able to demonstrate that cytoplasmatic VEGFA/(165)b expression is higher in invasive breast cancer tumor cells than in normal tissues or stroma. These examples show that the detection of VEGF splice variants can be performed also on the protein level in formalin fixed tissues. Although no quantitative conclusions can be drawn, these results may be the starting point for further studies at a quantitative level, which can be a major step towards the design of targeted antibody-based (breast) cancer therapies

Cognitive Change in a Diverse Group of Individuals Aged 90+: The LifeAfter90 Study

Abstract: Background: The oldest‐old are the fastest growing segment of the elderly population but very little is known about cognition in this age group; particularly in diverse populations. Our goal was to evaluate if domain specific cognitive change was different across different ethnoracial groups in those aged 90+. Method: LifeAfter90 (LA90) is an ongoing cohort of participants aged 90+ who are long‐term members of Kaiser Permanente Northern California participants. Participants (n = 984) were interviewed every 6 months for up to 3.5 years (1‐7 visits). Executive Function (EF) and Verbal Episodic Memory (VEM) were measured every six months using z‐standardized Spanish English Neuropsychological Assessment Scale. Racial/ethnic identify (Asian, Black, Latino, or White participants) was used in linear mixed models with random slopes and intercepts adjusting for baseline age, gender, education, interview mode, and practice effects. Result: Participants were 20% Latino, 23% Black, 24% Asian, 27% White, and 7% other individuals with a mean age of 92.4 (SD = 2.3) and a mean follow up time 1.1 years (Table 1). 39% of the cohort were men, 35% were college educated, and 29% were high school or less educated. Average annual change in EF was ‐0.06 (95% CI: ‐0.12, ‐0.00). Stratified models with Latino as the reference group showed White participants had significantly greater decline in EF (β = ‐0.13; 95%CI:‐0.20,‐0.06), followed by Asian participants (β = ‐0.09; 95%CI:‐0.17,‐0.01). EF scores among Black participants and participants who identified as other declined at a similar rate as Latino participants (β = ‐0.03; 95%CI:‐0.11,‐0.05; β = 0.00; 95%CI:‐0.10, 0.11; respectively) (Table 2: model 2). VEM had an annual change of ‐0.26 (95%CI: ‐0.40, ‐0.13), but there were no significant differences across ethnoracial groups in rate of decline. Conclusion: In this population of individuals aged 90+, decline in EF over the study period varied across ethnoracial group with White participants experiencing the fastest decline and Black, Latino, and other participants experiencing the slowest decline. Continued follow up will identify if there are differences in risk of cognitive impairment in this diverse population of oldest‐old. The results suggest the disparities in cognitive aging for those aged 90+ don’t mirror disparities seen in younger‐elderly ages

Cerebral perfusion and amyloidosis in the oldest‐old

IntroductionIn a nested case-control study, we examined how cerebral perfusion relates to cognitive status and amyloid in the oldest-old (i.e., 90 years of age and older).MethodsStudy participants included 113 dementia-free older adults (76 cognitively normal [CN]; 37 cognitively impaired, no dementia [CIND]) from the 90+ Study (mean age = 92.9, SD = 2.4). We quantified regional perfusion from arterial spin labeling-MRI (magnetic resonance imaging) and amyloid deposition from florbetapir-positron emission tomography (PET) in a region comprising the posterior cingulate and precuneus (PCC+PCu), and additionally quantified perfusion in other regions important for cognitive decline (medial temporal lobe, inferior parietal lobe, and orbitofrontal cortex).ResultsParticipants with CIND displayed lower perfusion in the PCC+PCu relative to participants who were CN, but there was no statistically significant difference between the groups in amyloid burden in this region. In addition, participants with CIND exhibited lower inferior parietal and higher orbitofrontal perfusion.DiscussionCerebral perfusion is related to cognitive status in the oldest-old independent of amyloidosis.HighlightsCerebral perfusion and amyloid positron emission tomography (PET) were measured in older adults: 90 years of age and older. Perfusion but not amyloid differed between cognitively impaired and normal groups. Frontal and parietal regions linked to cognitive decline had altered perfusion. Perfusion is related to cognitive status in the oldest-old independent of amyloid

Serological inflammation markers and their association with cognition in the oldest old; The 90+ Study

BackgroundRecent studies in the younger old have identified associations between cognitive performance and markers of inflammation, including interleukin-6 (IL-6) and erythrocyte sedimentation rate (ESR). These associations remain unexplored in the oldest old (age 90+), an age group most vulnerable to dementia. In addition, no studies have examined if amyloid burden impacts these associations. This study aims to: (1) examine the associations between inflammatory markers (IL-6, ESR) and cognitive performance in individuals age 90+ and (2) to examine if amyloid burden impacts these associations.MethodParticipants with at least one plasma measure of inflammation and amyloid burden measured by positron emission tomography (PET) were selected from The 90+ Study (n = 112 for IL-6, n = 123 for ESR). Cognitive measures included (1) global cognitive score defined as the average of the standardized scores of Mini-Mental State Examination (MMSE) and Modified MMSE (3MS), and (2) memory score, that was the average of the standardized scores of California Verbal Learning Test (CVLT) and memory items of 3MS. PET amyloid burden was measured by standardized uptake value ratio (SUVR). We examined the associations between IL-6 and ESR (independent variables) with cognitive measures (dependent variable) using linear regression models. Two models were implemented: first, without adjustment and second, with adjustment for amyloid. Both models were also adjusted for age at blood draw, sex, and education (college/no college). We additionally adjusted for amyloid burden and years between blood draw and PET scan in the second model.ResultMean age at blood draw was 94.7±2.8 and most participants were female (63.4%) and white (92.7%) (Table 1). In model 1, for both IL-6 and ESR, higher levels were significantly associated with lower global cognitive scores (Table 2). Only IL-6 was significantly associated with memory score (Table 2). Amyloid adjustment in model 2 had little effect on our results (Table 2).ConclusionThis study suggests that systemic inflammation could contribute to cognitive performance in individuals aged 90 and older. Additionally, this influence may be linked to a process not attributed to amyloid. Further research is warranted to explore the role of inflammation in non-Alzheimer's disease dementias

Evaluating the updated LATE‐NC staging criteria using data from NACC

IntroductionLimbic-predominant age-related TAR DNA-binding protein of 43 kDa encephalopathy neuropathologic change (LATE-NC) staging criteria were updated in 2023. We evaluated this updated staging using National Alzheimer's Coordinating Center data.MethodsWe examined associations of LATE-NC stages with cognition and other neuropathologic changes (NCs), and with cognition while accounting for other NCs, using multilevel regression models.ResultsOf 1352 participants, 502 (37%) had LATE-NC (23% stage 1a, 6% stage 1b, 58% stage 2, 13% stage 3). LATE-NC stages were associated with cognition, hippocampal sclerosis of aging (HS-A), Alzheimer's disease NC (ADNC), Lewy bodies (LBs), and hippocampal atrophy. While stage 1b was associated with cognition and HS-A consistent with other stages, it was not associated with ADNC or LBs. All LATE-NC stages remained significantly associated with worse cognition when accounting for other NCs.DiscussionThe updated LATE-NC staging criteria capture variations in early TDP-43 pathology spread which are consequential for cognition and associations with other NCs.HighlightsWe applied the updated limbic-predominant age-related TAR DNA-binding protein of 43 kDa encephalopathy neuropathologic change (LATE-NC) staging criteria to data from the National Alzheimer's Coordinating Center. LATE-NC stage 1b was identified in 22% of participants with stage 1. In contrast to other LATE-NC stages, stage 1b was not associated with Alzheimer's disease neuropathologic change (ADNC) or Lewy bodies. Stages 1a and 1b were significantly associated with dementia and memory impairment. Stages 1b+ were more strongly tied to dementia than all other neuropathologic changes except high likelihood ADNC

Neuropathologic Burden and Dementia in Nonagenarians and Centenarians

Background and objectivesThe aim of this study was to compare 2 large clinicopathologic cohorts of participants aged 90+ and to determine whether the association between neuropathologic burden and dementia in these older groups differs substantially from those seen in younger-old adults.MethodsAutopsied participants from The 90+ Study and Adult Changes in Thought (ACT) Study community-based cohort studies were evaluated for dementia-associated neuropathologic changes. Associations between neuropathologic variables and dementia were assessed using logistic or linear regression, and the weighted population attributable fraction (PAF) per type of neuropathologic change was estimated.ResultsThe 90+ Study participants (n = 414) were older (mean age at death = 97.7 years) and had higher amyloid/tau burden than ACT <90 (n = 418) (mean age at death = 83.5 years) and ACT 90+ (n = 401) (mean age at death = 94.2 years) participants. The ACT 90+ cohort had significantly higher rates of limbic-predominant age-related TDP-43 encephalopathy (LATE-NC), microvascular brain injury (μVBI), and total neuropathologic burden. Independent associations between individual neuropathologic lesions and odds of dementia were similar between all 3 groups, with the exception of μVBI, which was associated with increased dementia risk in the ACT <90 group only (odds ratio 1.5, 95% CI 1.2-1.8, p < 0.001). Weighted PAF scores indicated that eliminating μVBI, although more prevalent in ACT 90+ participants, would have little effect on dementia. Conversely, eliminating μVBI in ACT <90 could theoretically reduce dementia at a similar rate to that of AD neuropathologic change (weighted PAF = 6.1%, 95% CI 3.8-8.4, p = 0.001). Furthermore, reducing LATE-NC in The 90+ Study could potentially reduce dementia to a greater degree (weighted PAF = 5.1%, 95% CI 3.0-7.3, p = 0.001) than either ACT cohort (weighted PAFs = 1.69, 95% CI 0.4-2.7).DiscussionOur results suggest that specific neuropathologic features may differ in their effect on dementia among nonagenarians and centenarians from cohorts with different selection criteria and study design. Furthermore, microvascular lesions seem to have a more significant effect on dementia in younger compared with older participants. The results from this study demonstrate that different populations may require distinct dementia interventions, underscoring the need for disease-specific biomarkers