Meeting Report: Aging Research and Drug Discovery

Aging is the single largest risk factor for most chronic diseases, and thus possesses large socioeconomic interest to continuously aging societies. Consequently, the field of aging research is expanding alongside a growing focus from the industry and investors in aging research. This year's 8th Annual Aging Research and Drug Discovery ARDD) meeting was organized as a hybrid meeting from August 30th to September 3rd 2021 with more than 130 attendees participating on-site at the Ceremonial Hall at University of Copenhagen, Denmark, and 1800 engaging online. The conference comprised of presentations from 75 speakers focusing on new research in topics including mechanisms of aging and how these can be modulated as well as the use of AI and new standards of practices within aging research. This year, a longevity workshop was included to build stronger connections with the clinical community

The neurobiology of mouse models syntenic to human chromosome 15q

Autism is a neurodevelopmental disorder that manifests in childhood as social behavioral abnormalities, such as abnormal social interaction, impaired communication, and restricted interest or behavior. Of the known causes of autism, duplication of human chromosome 15q11–q13 is the most frequently associated cytogenetic abnormality. Chromosome 15q11–q13 is also known to include imprinting genes. In terms of neuroscience, it contains interesting genes such as Necdin, Ube3a, and a cluster of GABAA subunits as well as huge clusters of non-coding RNAs (small nucleolar RNAs, snoRNAs). Phenotypic analyses of mice genetically or chromosomally engineered for each gene or their clusters on a region of mouse chromosome seven syntenic to human 15q11–q13 indicate that this region may be involved in social behavior, serotonin metabolism, and weight control. Further studies using these models will provide important clues to the pathophysiology of autism. This review overviews phenotypes of mouse models of genes in 15q11–q13 and their relationships to autism

Subthreshold amyloid and its biological and clinical meaning Long way ahead

The development of in vivo imaging of the pathologic hallmark of Alzheimer disease (AD), beta-amyloid (A beta), altered the framing of its pathophysiology and formulation of inclusion criteria for clinical trials. Recent evidence suggests that in vivo measures of A beta deposition below a threshold indicative of A beta positivity carry critical information on future cognitive decline and accumulation of AD pathology, potentially already at a younger age. Here, we integrate the existing literature on histopathology of A beta and its convergence and divergence with in vivo A beta imaging. The evidence presented amounts to a reconceptualization, in which we advocate for a closer look into A beta accumulation rates in earlier life, the factors that promote accumulation, comparative studies with different markers of A beta, and longitudinal designs to elucidate when AD pathology rises and how it shifts from benign to malignant stages that ultimately define AD. These efforts open a new window of opportunity for disease-modifying interventions

Molecular imaging in early diagnosis, differential diagnosis and follow-up of patients with neurodegenerative diseases

Purpose Current disease models suggest that many neurodegenerative disorders are associated with pathological protein aggregations that start to develop in the brain long before the onset of clinical symptoms. Therefore, biomarkers allowing early and reliable characterization of neurodegenerative disease are required. Here we illustrate the potential value of neuroimaging procedures by means of selected examples. Methods Multimodal imaging data of exemplary patients who underwent FDG, Amyloid and AV-1451-PET, FPCIT-SPECT and MRI imaging in the routine clinical workup in our department is presented and the currently available literature on the topic of imaging in neurodegenerative diseases was reviewed. Results The complementary value of the applied imaging methods is demonstrated in pairs of representative cases. Depending on the clinical question, individual methods or a meaningful multimodal combination is required to achieve optimal diagnostic benefit. Conclusion Imaging biomarkers have high potential for early diagnosis, differential diagnosis and follow-up of patients with neurodegenerative diseases already and will pathology-targeted therapies will be evaluated in clinical trials

Amyloid deposition in younger adults is linked to episodic memory performance

Objective: To examine the relationship of beta-amyloid (A beta) deposition to episodic memory in younger (30-49 years), middle-older (50-69 years), and older adults (70-89 years). We hypothesized that subclinical levels of amyloid would be linked to memory in adults across the lifespan in a dose-dependent fashion. Of great interest was whether, within the younger group, a relationship between amyloid level and memory performance could be established. Methods: A total of 147 participants from the Dallas Lifespan Brain Study, aged 30-89, underwent PET imaging with F-18-florbetapir and cognitive assessment. We assessed the relationship between age group and amyloid and tested whether A beta differentially affected memory performance across the 3 age groups. Results: We report a significant association of age to amyloid burden for younger and middle-older adults (r = 0.57 and 0.28, respectively), but not for the oldest group, although absolute level of amyloid increased across the age groups. Importantly, the youngest group showed a significant decrease in recall (r = 20.47, p = 0.004) and recognition memory (r = -0.48, p = 0.003) as a function of increases in A beta burden, whereas this relationship was absent in the middle-older and oldest group (all p. 0.23). Conclusions: These results indicate that variance in subclinical levels of A beta in younger adults is meaningful, and suggest that higher SUVRs relative to one's peers at a younger age is not entirely benign

Entorhinal Tau Predicts Hippocampal Activation and Memory Deficits in Alzheimer's Disease

Background: To date, it remains unclear how amyloid plaques and neurofibrillary tangles are related to neural activation and, consequently, cognition in Alzheimer's disease (AD). Recent findings indicate that tau accumulation may drive hippocampal hyperactivity in cognitively normal aging, but it remains to be elucidated how tau accumulation is related to neural activation in AD. Objective: To determine whether the association between tau accumulation and hippocampal hyperactivation persists in mild cognitive impairment (MCI) and mild dementia or if the two measures dissociate with disease progression, we investigated the relationship between local tau deposits and memory-related neural activation in MCI and mild dementia due to AD. Methods: Fifteen patients with MCI or mild dementia due to AD underwent a neuropsychological assessment and performed an item memory task during functional magnetic resonance imaging. Cerebral tau accumulation was assessed using positron emission tomography and [F-18]-AV-1451. Results: Entorhinal, but not global tau accumulation, was highly correlated with hippocampal activation due to visual item memory encoding and predicted memory loss over time. Neural activation in the posterior cingulate cortex and the fusiform gyrus was not significantly correlated with tau accumulation. Conclusion: These findings extend previous observations in cognitively normal aging, demonstrating that entorhinal tau continues to be closely associated with hippocampal hyperactivity and memory performance in MCI and mild dementia due to AD. Furthermore, data suggest that this association is strongest in medial temporal lobe structures. In summary, our data provide novel insights into the relationship of tau accumulation to neural activation and memory in AD