Predictors of hippocampal tauopathy in people with and at risk for human immunodeficiency virus infection.

Combination antiretroviral therapy (cART) has extended lifespans of people living with HIV (PWH), increasing both the risk for age-related neuropathologies and the importance of distinguishing effects of HIV and its comorbidities from neurodegenerative disorders. The accumulation of hyperphosphorylated tau (p-tau) in hippocampus is a common degenerative change, with specific patterns of hippocampal subfield vulnerability observed in different disease contexts. Currently, associations between chronic HIV, its comorbidities, and p-tau burden and distribution in the hippocampus are unexplored. We used immunohistochemistry with antibody AT8 to analyze hippocampal p-tau in brain tissues of PWH (n = 71) and HIV negative controls (n = 25), for whom comprehensive clinical data were available. Using a morphology-based neuroanatomical segmentation protocol, we annotated digital slide images to measure percentage p-tau areas in the hippocampus and its subfields. Factors predicting p-tau burden and distribution were identified in univariate analyses, and those with significance at p ≤ 0.100 were advanced to multivariable regression. The patient sample had a mean age of 61.5 years. Age predicted overall hippocampal p-tau burden. Subfield p-tau predictors were for Cornu Ammonis (CA)1, age; for CA2 and subiculum, seizure history; for CA3, seizure history and head trauma; and for CA4/dentate, history of hepatitis C virus (HCV) infection. In this autopsy sample, hippocampal p-tau burden and distribution were not predicted by HIV, viral load, or immunologic status, with viral effects limited to associations between HCV and CA4/dentate vulnerability. Hippocampal p-tau pathologies in cART-era PWH appear to reflect age and comorbidities, but not direct effects of HIV infection.

Histopathologic brain age estimation via multiple instance learning.

Understanding age acceleration, the discordance between biological and chronological age, in the brain can reveal mechanistic insights into normal physiology as well as elucidate pathological determinants of age-related functional decline and identify early disease changes in the context of Alzheimer's and other disorders. Histopathological whole slide images provide a wealth of pathologic data on the cellular level that can be leveraged to build deep learning models to assess age acceleration. Here, we used a collection of digitized human post-mortem hippocampal sections to develop a histological brain age estimation model. Our model predicted brain age within a mean absolute error of 5.45 ± 0.22 years, with attention weights corresponding to neuroanatomical regions vulnerable to age-related changes. We found that histopathologic brain age acceleration had significant associations with clinical and pathologic outcomes that were not found with epigenetic based measures. Our results indicate that histopathologic brain age is a powerful, independent metric for understanding factors that contribute to brain aging.

The relationship between hippocampal amyloid beta burden and spatial distribution of neurofibrillary degeneration.

INTRODUCTION: Neurofibrillary degeneration in Alzheimer's disease (AD) typically involves the entorhinal cortex and CA1 subregion of the hippocampus early in the disease process, whereas in primary age-related tauopathy (PART), there is an early selective vulnerability of the CA2 subregion. METHODS: Image analysis-based quantitative pixel assessments were used to objectively evaluate amyloid beta (Aß) burden in the medial temporal lobe in relation to the distribution of hyperphosphorylated-tau (p-tau) in 142 cases of PART and AD. RESULTS: Entorhinal, CA1, CA3, and CA4 p-tau deposition levels are significantly correlated with Aß burden, while CA2 p-tau is not. Furthermore, the CA2/CA1 p-tau ratio is inversely correlated with Aß burden and distribution. In addition, cognitive impairment is correlated with overall p-tau burden. DISCUSSION: These data indicate that the presence and extent of medial temporal lobe Aß may determine the distribution and spread of neurofibrillary degeneration. The resulting p-tau distribution patterns may discriminate between PART and AD. HIGHLIGHTS: Subregional hyperphosphorylated-tau (p-tau) distribution is influenced by hippocampal amyloid beta burden. Higher CA2/CA1 p-tau ratio is predictive of primary age-related tauopathy-like neuropathology. Cognitive function is correlated with the overall hippocampal p-tau burden.

Aß Deposits in the Neocortex of Adult and Infant Hypoxic Brains, Including in Cases of COVID-19.

The brain of a 58-year-old woman was included as a civilian control in an ongoing autopsy study of military traumatic brain injury (TBI). The woman died due to a polysubstance drug overdose, with Coronavirus Disease 2019 (COVID-19) serving as a contributing factor. Immunohistochemical stains for ß-amyloid (Aß), routinely performed for the TBI study, revealed numerous, unusual neocortical Aß deposits. We investigated the autopsied brains of 10 additional young patients (<60 years old) who died of COVID-19, and found similar Aß deposits in all, using two different Aß antibodies across three different medical centers. The deposits failed to stain with Thioflavin-S. To investigate whether or not these deposits formed uniquely to COVID-19, we applied Aß immunostains to the autopsied brains of COVID-19-negative adults who died with acute respiratory distress syndrome and infants with severe cardiac anomalies, and also biopsy samples from patients with subacute cerebral infarcts. Cortical Aß deposits were also found in these cases, suggesting a link to hypoxia. The fate of these deposits and their effects on function are unknown, but it is possible that they contribute to the neurocognitive sequelae observed in some COVID-19 patients. Our findings may also have broader implications concerning hypoxia and its role in Aß deposition in the brain.

SUDEP among young adults in the San Diego County Medical Examiner Office.

Excess mortality due to epilepsy is greatest among young adults. However, the relative proportions of sudden unexpected death in epilepsy (SUDEP) and other epilepsy-related causes of death are not well defined. We prospectively adjudicated cause of death in all 18- to 45-year-olds with a history of seizure/epilepsy who underwent medicolegal investigation in San Diego County between 2014 and 2017. We identified 108 decedents with definite or probable epilepsy; 62% died from an epilepsy-related cause. SUDEP accounted for 42.6% (N = 46) of deaths, which were usually unwitnessed deaths, at home in bed. Other frequent causes of death were drug overdose (N = 23), suicide (N = 8), trauma (N = 8), and drowning (N = 6). SUDEP autopsies were similar to those of decedents from other causes. Most deaths in young adults with epilepsy that undergo medico-legal investigation are epilepsy-related, and SUDEP is the leading cause. Improved seizure control can potentially save many lives.