Faculty Bibliography

Tau interacts with multiple heterogeneous nuclear ribonucleoproteins (hnRNPs)-a family of RNA binding proteins that regulate multiple known cellular functions, including mRNA splicing, mRNA transport, and translation regulation. We have previously demonstrated particularly significant interactions between phosphorylated tau and three hnRNPs (hnRNP A1, hnRNP A2B1, and hnRNP K). Although multiple hnRNPs have been previously implicated in tauopathies, knowledge of whether these hnRNPs colocalize with tau aggregates or show cellular mislocalization in disease is limited. Here, we performed a neuropathological study examining the colocalization between hnRNP A1, hnRNP A2B1, hnRNP K, and phosphorylated tau in two brain regions (hippocampus and frontal cortex) in six disease groups (Alzheimer's disease, mild cognitive impairment, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and controls). Contrary to expectations, hnRNP A1, hnRNP A2B1, and hnRNP K did not colocalize with AT8-immunoreactive phosphorylated tau pathology in any of the tauopathies examined. However, we did observe significant cellular mislocalization of hnRNP A1, hnRNP A2B1 and hnRNP K in tauopathies, with unique patterns of mislocalization observed for each hnRNP. These data point to broad dysregulation of hnRNP A1, A2B1 and K across tauopathies with implications for disease processes and RNA regulation.

IMPORTANCE/UNASSIGNED:The lack of an in vivo measure for α-synuclein (α-syn) pathology until recently has limited thorough characterization of its brain atrophy pattern, especially during early disease stages. OBJECTIVE/UNASSIGNED:To assess the association of state-of-the-art cerebrospinal fluid (CSF) seed amplification assays (SAA) α-syn positivity (SAA α-syn+) with magnetic resonance imaging (MRI) structural measures, across the continuum from clinically unimpaired (CU) to cognitively impaired (CI) individuals, in 3 independent cohorts, and separately in CU and CI individuals, the latter reflecting a memory clinic population. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:Cross-sectional data were used from the Swedish BioFINDER-2 study (inclusion, 2017-2023) as the discovery cohort and the Swedish BioFINDER-1 study (inclusion, 2007-2015) and Alzheimer's Disease Neuroimaging Initiative (ADNI; inclusion 2005-2022) as replication cohorts. All cohorts are from multicenter studies, but the BioFINDER cohorts used 1 MRI scanner. CU and CI individuals fulfilling inclusion criteria and without missing data points in relevant metrics were included in the study. All analyses were performed from 2023 to 2024. EXPOSURES/UNASSIGNED:Presence of α-syn pathology, estimated by baseline CSF SAA α-syn. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcomes were cross-sectional structural MRI measures either through voxel-based morphometry (VBM) or regions of interest (ROI) including an automated pipeline for cholinergic basal forebrain nuclei CH4/4p (nucleus basalis of Meynert [NBM]) and CH1/2/3. Secondary outcomes were domain-specific cross-sectional cognitive measures. Analyses were adjusted for CSF biomarkers of Alzheimer pathology. RESULTS/UNASSIGNED:A total of 2961 participants were included in this study: 1388 (mean [SD] age, 71 [10] years; 702 female [51%]) from the BioFINDER-2 study, 752 (mean [SD] age, 72 [6] years; 406 female [54%]) from the BioFINDER-1 study, and 821 (mean [SD] age, 75 [8] years; 449 male [55%]) from ADNI. In the BioFINDER-2 study, VBM analyses in the whole cohort revealed a specific association between SAA α-syn+ and the cholinergic NBM, even when adjusting for Alzheimer copathology. ROI-based analyses in the BioFINDER-2 study focused on regions involved in the cholinergic system and confirmed that SAA α-syn+ was indeed independently associated with smaller NBM (β = -0.271; 95% CI, -0.399 to -0.142; P <.001) and CH1/2/3 volumes (β = -0.227; 95% CI, -0.377 to -0.076; P =.02). SAA α-syn+ was also independently associated with smaller NBM volumes in the separate CU (β = -0.360; 95% CI, -0.603 to -0.117; P =.03) and CI (β = -0.251; 95% CI, -0.408 to -0.095; P =.02) groups. Overall, the association between SAA α-syn+ and NBM volume was replicated in the BioFINDER-1 study and ADNI cohort. In CI individuals, NBM volumes partially mediated the association of SAA α-syn+ with attention/executive impairments in all cohorts (BioFINDER-2, β = -0.017; proportion-mediated effect, 7%; P =.04; BioFINDER-1, β = -0.096; proportion-mediated effect, 19%; P =.04; ADNI, β = -0.061; proportion-mediated effect, 20%; P =.007). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cohort study, SAA α-syn+ was consistently associated with NBM atrophy already during asymptomatic stages. Further, in memory clinic CI populations, SAA α-syn+ was associated with NBM atrophy, which partially mediated α-syn-induced attention/executive impairment.

BACKGROUND:Pain is a frequent yet poorly characterized symptom of multiple system atrophy (MSA). Understanding the factors influencing pain and its burden is crucial for improving the symptomatic treatment and quality of life of MSA individuals. OBJECTIVE:This study aimed at assessing the prevalence, characteristics, and current treatment strategies for pain in MSA. METHODS:A community-based, online survey was conducted from February to May 2023. Invitations were extended to MSA individuals and informal MSA caregivers through patient advocacies and social media. RESULTS:We included 190 persons with MSA and 114 caregivers. Eighty-seven percent of MSA individuals reported pain, which was more prevalent among women (odds ratio [OR]: 6.38 [95% confidence interval, CI: 1.27-32.08], P = 0.025) and low-income groups (OR: 5.02 [95% CI: 1.32-19.08], P = 0.018). Neck and shoulders (58%), back (45%), and legs (45%) were mostly affected. In the neck and shoulders, pain was associated with MSA core features, like orthostatic intolerance (OR: 4.80 [95% CI: 1.92-12.02], P = 0.001) and antecollis (OR: 3.24 [95% CI: 1.54-6.82], P = 0.002). Seventy-six percent of individuals experiencing pain received treatment, mostly nonsteroidal anti-inflammatory drugs (47%), acetaminophen (39%), and opioids (28%). Only 53% of respondents reported at least partial satisfaction with their current pain management. Pain mostly impacted work, household activities, and hobbies of MSA individuals, and caregivers' social activities. CONCLUSIONS:Pain is more prevalent than previously reported in MSA and particularly affects women and low-income groups. Despite its frequency, pain management remains suboptimal, highlighting an urgent therapeutic need, likely entailing an optimized management of MSA core motor and non-motor features. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Whether high-frequency phase-locked oscillations facilitate integration ('binding') of information across widespread cortical areas is controversial. Here we show with intracranial electroencephalography that cortico-cortical co-ripples (~100-ms-long ~90 Hz oscillations) increase during reading and semantic decisions, at the times and co-locations when and where binding should occur. Fusiform wordform areas co-ripple with virtually all language areas, maximally from 200 to 400 ms post-word-onset. Semantically specified target words evoke strong co-rippling between wordform, semantic, executive and response areas from 400 to 800 ms, with increased co-rippling between semantic, executive and response areas prior to correct responses. Co-ripples were phase-locked at zero lag over long distances (>12 cm), especially when many areas were co-rippling. General co-activation, indexed by non-oscillatory high gamma, was mainly confined to early latencies in fusiform and earlier visual areas, preceding co-ripples. These findings suggest that widespread synchronous co-ripples may assist the integration of multiple cortical areas for sustained periods during cognition.

Alzheimer's disease (AD) is an incurable and progressive neurodegenerative disease with increasing prevalence worldwide. Previous trials of anti-amyloid and anti-tau immunotherapy indicate that additional research needs to be conducted on other mechanisms to find curative or disease-modifying therapy. This review focuses on apolipoprotein E (ApoE), a critical protein in brain lipid metabolism that acts specifically in the clearance and transport of lipids and cholesterol. The ApoE4 allele confers substantial gene dose-dependent risk of developing AD and lowers the age of onset of AD, although the mechanisms of influence remain incompletely understood. The other isoforms bring different levels of AD risk. ApoE2 is protective while ApoE3 is the most common isoform and is considered neutral. An overview is presented of the latest information on the role of ApoE in AD pathogenesis with an emphasis on pathways that are involved in AD development and interactions with crucial processes in different cell types in the brain. Elucidating the key interactions of ApoE with multiple aspects of brain function can be useful for designing novel ApoE-targeted therapeutic approaches.

OBJECTIVE:To characterize the experience of people with epilepsy and aligned healthcare workers (HCWs) during the first 18 months of the COVID-19 pandemic and compare experiences in high-income countries (HICs) with non-HICs. METHODS:Separate surveys for people with epilepsy and HCWs were distributed online in April 2020. Responses were collected to September 2021. Data were collected for COVID-19 infections, the effect of COVID-related restrictions, access to specialist help for epilepsy (people with epilepsy), and the impact of the pandemic on work productivity (HCWs). The frequency of responses for non-HICs and HICs were compared using non-parametric Chi-square tests. RESULTS:Two thousand one hundred and  five individuals with epilepsy from 53 countries and 392 HCWs from 26 countries provided data. The same proportion of people with epilepsy in non-HICs and HICs reported COVID-19 infection (7%). Those in HICs were more likely to report that COVID-19 measures had affected their health (32% vs. 23%; p < 0.001). There was no difference between non-HICs and HICs in the proportion who reported difficulty in obtaining help for epilepsy. HCWs in non-HICs were more likely to report COVID-19 infection than those in HICs (18% vs 6%; p = 0.001) and that their clinical work had been affected by concerns about contracting COVID-19, lack of personal protective equipment, and the impact of the pandemic on mental health (all p < 0.001). Compared to pre-pandemic practices, there was a significant shift to remote consultations in both non-HICs and HICs (p < 0.001). SIGNIFICANCE/CONCLUSIONS:While the frequency of COVID-19 infection was relatively low in these data from early in the pandemic, our findings suggest broader health consequences and an increased psychosocial burden, particularly among HCWs in non-HICs. Planning for future pandemics should prioritize mental healthcare alongside ensuring access to essential epilepsy services and expanding and enhancing access to remote consultations. PLAIN LANGUAGE SUMMARY/CONCLUSIONS:We asked people with epilepsy about the effects of COVID-19 on their health and healthcare. We wanted to compare responses from people in high-income countries and other countries. We found that people in high-income countries and other countries had similar levels of difficulty in getting help for their epilepsy. People in high-income countries were more likely to say that their general health had been affected. Healthcare workers in non-high-income settings were more likely to have contracted COVID-19 and have the care they deliver affected by the pandemic. Across all settings, COVID-19 associated with a large shift to remote consultations.

Alzheimer's disease (AD) is a devastating, age-associated neurodegenerative disorder and the most common cause of dementia. The clinical continuum of AD spans from preclinical disease to subjective cognitive decline, mild cognitive impairment, and dementia stages (mild, moderate, and severe). Neuropathologically, AD is defined by the accumulation of amyloid β (Aβ) into extracellular plaques in the brain parenchyma and in the cerebral vasculature, and by abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Development of treatment approaches that prevent or even reduce the cognitive decline because of AD has been slow compared to other major causes of death. Recently, the United States Food and Drug Administration gave full approval to 2 different Aβ-targeting monoclonal antibodies. However, this breakthrough disease modifying approach only applies to a limited subset of patients in the AD continuum and there are stringent eligibility criteria. Furthermore, these approaches do not prevent progression of disease, because other AD-related pathologies, such as NFTs, are not directly targeted. A non-mutually exclusive alternative is to address lifestyle interventions that can help reduce the risk of AD and AD-related dementias (ADRD). It is estimated that addressing such modifiable risk factors could potentially delay up to 40% of AD/ADRD cases. In this review, we discuss some of the many modifiable risk factors that may be associated with prevention of AD/ADRD and/or increasing brain resilience, as well as other factors that may interact with these modifiable risk factors to influence AD/ADRD progression. ANN NEUROL 2024.