Faculty Bibliography

Almost all individuals with Down Syndrome (DS) develop Alzheimer's disease (AD) by mid to late life. However, the degree to which AD in DS shares pathological changes with sporadic late-onset AD (LOAD) and autosomal dominant AD (ADAD) beyond core AD biomarkers such as amyloid-β (Aβ) and tau is unknown. Here, we used proteomics of cerebrospinal fluid from individuals with DS (n = 229) in the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) cohort to assess the evolution of AD pathophysiology from asymptomatic to dementia stages and compared the proteomic biomarker changes in DS to those observed in LOAD and ADAD. Although many proteomic alterations were shared across DS, LOAD, and ADAD, DS demonstrated more severe changes in immune-related proteins, extracellular matrix pathways, and plasma proteins likely related to blood-brain barrier dysfunction compared to LOAD. These changes were present in young adults with DS prior to the onset of Aβ or tau pathology, suggesting they are associated with trisomy 21 and may serve as risk factors for DSAD. DSAD showed an earlier increase in markers of axonal and white matter pathology and earlier changes in markers potentially associated with cerebral amyloid angiopathy compared to ADAD. The unique features of DSAD may have important implications for treatment strategies in this population.

Parkinson's disease (PD) is a neurodegenerative disease characterized by motor and non-motor symptoms that progressively deteriorate and for which there is no disease-modifying pharmacological treatment. Exercise is widely recommended for individuals with PD due to its potential neuroprotective benefits. However, the mechanisms underlying these exercise-induced effects in PD remain poorly understood. Analyzing fluid biomarkers responsive to exercise could offer valuable insights into the mechanisms by which exercise impacts PD and aid in optimizing exercise prescriptions for individuals with PD. This review explores exercise-responsive biomarkers categorized into three key groups-neurotrophic, inflammatory, and neuroendocrine markers. It highlights both well-validated biomarkers and candidates with promising potential. We also highlight key biomarkers linked to PD pathology, such as α-synuclein, and their potential connection to exercise based on current evidence. Comprehensive characterization of these biomarkers will advance our understanding of the biological effects of exercise in PD, enabling mechanism-based and objective measures to evaluate exercise response in future clinical trials and its impact on PD signs and symptoms.

Naturalistic electrocorticography (ECoG) data are a rare but essential resource for studying the brain's linguistic capabilities. ECoG offers high temporal resolution suitable for investigating processes at multiple temporal timescales and frequency bands. It also provides broad spatial coverage, often along critical language areas. Here, we share a dataset of nine ECoG participants with 1,330 electrodes listening to a 30-minute audio podcast. The richness of this naturalistic stimulus can be used for various research questions, from auditory perception to narrative integration. In addition to the neural data, we extracted linguistic features of the stimulus ranging from phonetic information to large language model word embeddings. We use these linguistic features in encoding models that relate stimulus properties to neural activity. Finally, we provide detailed tutorials for preprocessing raw data, extracting stimulus features, and running encoding analyses that can serve as a pedagogical resource or a springboard for new research.

BACKGROUND:Haploinsufficiency of the bromodomain PHD finger transcription factor (BPTF) gene, essential in chromatin remodeling, leads to a neurodevelopmental disorder characterized by dysmorphic facies, distal limb anomalies, neurological disturbances, epilepsy, and gastrointestinal symptoms. METHODS:Families with BPTF-related neurodevelopmental disorders, with or without gastrointestinal symptoms, were recruited through an international collaboration. Data were collected via questionnaires on demographics, clinical features, genetics, and comorbidities, focusing on cyclical vomiting syndrome (CVS). CVS was diagnosed using criteria from the International Classification of Headache Disorders, 3rd edition (ICHD-3). Genetic variants were analyzed for pathogenicity, and effectiveness of therapies was assessed. RESULTS:We enrolled 15 individuals with likely pathogenic/pathogenic BPTF variants (median age: 8.8 years). Three individuals (20%) were diagnosed with CVS, and an additional four individuals (26.7%) met at least three of the ICHD-3 criteria for CVS. Among these seven individuals, the median age at onset of recurrent vomiting episodes was 3 years. In all seven individuals, recurrent vomiting episodes, typically lasting under an hour, were triggered by poor sleep (50%) and fever (66.7%). Acute therapy (ondansetron or domperidone) was administered in 42.8% of cases, and prophylactic therapy was provided in 57.1% of cases with cyproheptadine, levetiracetam combined with lamotrigine, and domperidone; all therapies were associated with clinical benefit. Episodes disrupted families' daily lives, causing emotional stress (85.7%) and routine disruptions (85.7%). CONCLUSIONS:This study broadens the syndromic phenotype associated with BPTF haploinsufficiency, highlighting CVS as a core feature. The findings raise clinician awareness, guide management, and enhance understanding of this rare condition.

BACKGROUND/UNASSIGNED:Posttraumatic stress disorder (PTSD) symptoms are common in people with cocaine use disorder (CUD), and even sub-threshold PSTD symptoms result in worse treatment outcomes. Difficulties with reward functioning may drive this comorbidity. Impairments in reward functioning are prominent in both PTSD and CUD and contribute to development of substance use problems after trauma. There are three distinct reward processes that may be involved in the PTSD/CUD overlap: consummatory reward (ability to experience pleasure), motivational reward (willingness to exert effort for rewards), and reward learning (adapting behavior based on reward history). Here we test whether impairments in these reward functions account for the relationship between PTSD and CUD symptoms. METHODS/UNASSIGNED:This is a secondary analysis of data from a clinical trial (NCT02773212) that measured of PTSD symptoms, CUD severity, consummatory reward, motivational reward, and reward learning in 53 treatment-seeking people with CUD. RESULTS/UNASSIGNED:Greater PTSD symptoms related to (1) more severe CUD and (2) less ability to learn from reward; however, impaired reward learning did not significantly account for the overlap in PTSD and CUD symptom severity. CONCLUSIONS/UNASSIGNED:The observed relationship between PTSD and CUD symptoms was not accounted for by reduced ability to experience pleasure from rewards, reduced motivation for rewards, or reduced ability to learn from rewards. Thus, treatments that attempt to enhance reward functioning seem unlikely to address this complex comorbidity.

INTRODUCTION/UNASSIGNED:Recent investigations have identified patients of African ancestry (AA) with Multiple Sclerosis (MS), who display more rapid B-cell repopulation after standard semi-annual infusions with an anti-CD20 monoclonal antibody for B cell depletion. In this study, we explored the immunologic and genetic factors, with, serum drug monitoring that may contribute to a faster rate of B-cell repletion that follows during recovery from treatment with anti-CD20 antibody. METHODS/UNASSIGNED:In AA MS patients treated with an anti-CD20 antibody that had early repopulation of peripheral blood B cells, we assessed for extrinsic factors, including the presence of anti-drug antibodies against ocrelizumab, which may contribute to early repletion. We also documented the associated serum drug levels. In addition, we examined for inheritance of intrinsic gene polymorphisms associated with B cell survival and immune function. RESULTS/UNASSIGNED:Our findings identified a subset of AA patients with early B cell repletion after anti-CD20 treatment associated with anti-drug antibodies and an absence of detectable drug. Furthermore, a separate set of AA patients with the early B cell repletion phenotype without anti-drug antibodies had significant over-representation of genetic polymorphisms that map to genes for the B cell survival factor, BAFF, to antibody-dependent cytotoxicity, and to pathways involved in inflammation, leukocyte activation and B cell differentiation. DISCUSSION/UNASSIGNED:In AA patients with MS, after anti-CD20 antibody treatment we found an unexpected high occurrence of early B cell replenishment. This was associated with the presence of anti-drug antibodies and/or specific genetic polymorphisms. Larger studies are now needed to determine whether these factors may lead to impaired therapeutic benefits of B cell targeted therapy and clinical progression, and these findings may be useful to guide future optimized personalized therapeutic strategies.

Since the first description of swelling of the optic nerve head in patients with increased intracranial pressure, our understanding of its pathogenesis has undergone significant changes. Early theories postulated that the swelling was caused by excessive extracellular fluid, but these views were disproved when electron microscopy showed that the swelling arose from dilated optic nerve axons, and autoradiography demonstrated blocked axonal transport at the posterior lamina cribrosa. This led to the currently prevailing view that the axonal swelling is caused by the damming back of axoplasm. However, this theory cannot account for the extent of swelling, its rate of development, and the variety of morphological changes in papilledema. It also cannot explain the differing patterns of swelling in papilledema and acute glaucoma despite identically located blockages of axonal transport. We conducted a biomechanical analysis, in which we calculated the stresses induced in a cylindrical nerve by external compression and the effect of these stresses on the nerve's axons and the axoplasm within them. We propose a new theory in which the axial gradient of tissue pressure causes displacement of axoplasm from the extraocular to the intraocular segment of the nerve, accounting for the intraocular axonal swelling. In addition, a sharply localized axial shear stress disrupts the axonal cytoskeleton to block axonal transport. Although the pressure gradient and the shear stress are both caused by the external compression of the nerve, they differ in their relative magnitudes across the nerve cross-section. The proposed hypothesis resolves the difficulties with the damming back hypothesis.

INTRODUCTION/BACKGROUND:Primary tauopathies, including corticobasal degeneration (CBD), Pick's disease (PiD), and progressive supranuclear palsy (PSP), have aggregated tau pathology in the brain. Many other proteins are likely altered in disease; however, these have not been well characterized. METHODS:We performed sarkosyl fractionation of post mortem human brain tissue to enrich soluble and insoluble proteins from CBD, PiD, and PSP cases (n = 5/group). We assessed differences in the soluble fraction, insoluble fraction, and protein solubility changes between diseases, followed by enrichment and correlation analysis. RESULTS:CBD and PiD showed the greatest proteomic similarity in both the soluble and insoluble fractions, while PSP was the most divergent in comparison to other diseases. We observed critical changes in the solubility of lysosomal regulators, postsynaptic proteins, the extracellular matrix (ECM), and mitochondrial proteins. DISCUSSION/CONCLUSIONS:We have contrasted the solubility patterns of proteins across three tauopathies for the first time. Protein solubility differences reveal divergence in disease processes. HIGHLIGHTS/CONCLUSIONS:Tau isoforms are differentially soluble in primary tauopathies PSP proteomics profile was the most divergent of the tauopathies examined SORT1 is highly insoluble in CBD and aggregates to different extents in tauopathies There are shifts in solubility for key signalling pathways; ROCK1 and JAK2 Unique lysosomal proteins are more insoluble in distinct tauopathies.