Relative Contributions of Mixed Pathologies to Cognitive and Functional Symptoms in Brain Donors Exposed to Repetitive Head Impacts.

OBJECTIVE: Exposure to repetitive head impacts (RHI) is associated with later-life cognitive symptoms and neuropathologies, including chronic traumatic encephalopathy (CTE). Cognitive decline in community cohorts is often due to multiple pathologies; however, the frequency and contributions of these pathologies to cognitive impairment in people exposed to RHI are unknown. Here, we examined the relative contributions of 13 neuropathologies to cognitive symptoms and dementia in RHI-exposed brain donors. METHODS: Neuropathologists examined brain tissue from 571 RHI-exposed donors and assessed for the presence of 13 neuropathologies, including CTE, Alzheimer disease (AD), Lewy body disease (LBD), and transactive response DNA-binding protein 43 (TDP-43) inclusions. Cognitive status was assessed by presence of dementia, Functional Activities Questionnaire, and Cognitive Difficulties Scale. Spearman rho was calculated to assess intercorrelation of pathologies. Additionally, frequencies of pathological co-occurrence were compared to a simulated distribution assuming no intercorrelation. Logistic and linear regressions tested associations between neuropathologies and dementia status and cognitive scale scores. RESULTS: The sample age range was 18-97 years (median = 65.0, interquartile range = 46.0-76.0). Of the donors, 77.2% had at least one moderate-severe neurodegenerative or cerebrovascular pathology. Stage III-IV CTE was the most common neurodegenerative disease (43.1%), followed by TDP-43 pathology, AD, and hippocampal sclerosis. Neuropathologies were intercorrelated, and there were fewer unique combinations than expected if pathologies were independent (p < 0.001). The greatest contributors to dementia were AD, neocortical LBD, hippocampal sclerosis, cerebral amyloid angiopathy, and CTE. INTERPRETATION: In this sample of RHI-exposed brain donors with wide-ranging ages, multiple neuropathologies were common and correlated. Mixed neuropathologies, including CTE, underlie cognitive impairment in contact sport athletes. ANN NEUROL 2024;95:314-324.

Limited Bedding and Nesting Induces Maternal Behavior Resembling Both Hypervigilance and Abuse.

Early life adversity (ELA) is associated with altered neural development and increased risk for the development of psychopathology across the lifespan. Rodent models of ELA are an important tool for investigating the possible mechanistic underpinnings of pathology development. We used a limited bedding and nesting model (LBN) to induce stress in the dam and alter dam-pup interactions during a sensitive period in early postnatal development. The primary characteristics previously identified in this model include fragmented and unpredictable maternal care and possibly neglect. However, previous studies have not considered the effects of this manipulation over the full circadian cycle and the evolution of changes of maternal behavior throughout the duration of the manipulation. In the current study, we leverage a novel continuous video monitoring setup to unobtrusively observe and subsequently analyze maternal behaviors. Through this more in-depth analysis, we discovered that LBN dams spent more time than control dams on their nest, returned to their nest more frequently than control dams, and showed intact maternal care. Importantly, a subset of LBN dams (~40%) engaged in abusive-like kicking, a behavioral pattern not previously identified in this paradigm. Exposure to ELA and abusive-like kicking were associated with differences in risk-taking behavior in adulthood. The LBN model of ELA may drive a more complex constellation of effects on maternal behavior driving a pattern of increased dam-pup interactions and increased abuse-like kicking behavior, with unique consequences for pup outcomes.