Faculty Bibliography

BACKGROUND:Family caregivers of people living with dementia have high caregiver strain and poor health consequences. Limited research exists on Lewy body dementia (LBD) caregivers and their specific comorbidities. This study aimed to (1) identify the prevalence of self-reported comorbidities among LBD caregivers and (2) contextualize these findings with historical data on caregivers of persons living with Alzheimer disease and associated disorders (ADADs). METHODS:In a national, online survey, LBD family caregivers completed the Self-Administered Comorbidity Questionnaire and we compared these findings with extant literature on ADAD caregiver comorbidities. RESULTS:Among 217 LBD caregivers, 84.3% were female, 39.1% were 64 years old or younger, and 66.8% had >2 years of caregiving experience. Caregivers self-identified as current (83.9%) or former (16.1%) caregivers. The most frequent comorbidities were hypertension (38.2%), depression (35.0%), back pain (34.1%), and arthritis (27.7%). LBD caregivers, particularly younger caregivers, had a higher prevalence of depression compared with ADAD caregivers and older adult populations, and back pain prevalence nearly equivalent to spinal cord injury caregivers. CONCLUSIONS:Our study is the first to illustrate and contextualize specific comorbidities among LBD caregivers. Understanding the causality and impact of these conditions will be critical in designing effective interventions to improve the lives of families affected by LBD.

Traumatic brain injury (TBI), Alzheimer's disease (AD), and epilepsy share proposed mechanisms of injury, including neuronal excitotoxicity, cascade signaling, and activation of protein biomarkers such as tau. Although tau is typically present intracellularly, in tauopathies, phosphorylated (p-) and hyper-phosphorylated (hp-) tau are released extracellularly, the latter leading to decreased neuronal stability and neurofibrillary tangles (NFTs). Tau cleavage at particular sites increases susceptibility to hyper-phosphorylation, NFT formation, and eventual cell death. The relationship between tau and inflammation, however, is unknown. In this review, we present evidence for an imbalanced endoplasmic reticulum (ER) stress response and inflammatory signaling pathways resulting in atypical p-tau, hp-tau and NFT formation. Further, we propose tau as a biomarker for neuronal injury severity in TBI, AD, and epilepsy. We present a hypothesis of tau phosphorylation as an initial acute neuroprotective response to seizures/TBI. However, if the underlying seizure pathology or TBI recurrence is not effectively treated, and the pathway becomes chronically activated, we propose a "tipping point" hypothesis that identifies a transition of tau phosphorylation from neuroprotective to injurious. We outline the role of amyloid beta (Aβ) as a "last ditch effort" to revert the cell to programmed death signaling, that, when fails, transitions the mechanism from injurious to neurodegenerative. Lastly, we discuss targets along these pathways for therapeutic intervention in AD, TBI, and epilepsy.

INTRODUCTION/UNASSIGNED:Brain metastases are the most common intracranial tumor diagnosed in adults. In patients treated with stereotactic radiosurgery, the incidence of post-treatment radionecrosis appears to be rising, which has been attributed to improved patient survival as well as novel systemic treatments. The impacts of concomitant immunotherapy and the interval between diagnosis and treatment on patient outcomes are unclear. METHODS/UNASSIGNED:This single institution, retrospective study consisted of patients who received single or multi-fraction stereotactic radiosurgery for intact brain metastases. Exclusion criteria included neurosurgical resection prior to treatment and treatment of non-malignant histologies or primary central nervous system malignancies. A univariate screen was implemented to determine which factors were associated with radionecrosis. The chi-square test or Fisher's exact test was used to compare the two groups for categorical variables, and the two-sample t-test or Mann-Whitney test was used for continuous data. Those factors that appeared to be associated with radionecrosis on univariate analyses were included in a multivariable model. Univariable and multivariable Cox proportional hazards models were used to assess potential predictors of time to local failure and time to regional failure. RESULTS/UNASSIGNED:A total of 107 evaluable patients with a total of 256 individual brain metastases were identified. The majority of metastases were non-small cell lung cancer (58.98%), followed by breast cancer (16.02%). Multivariable analyses demonstrated increased risk of radionecrosis with increasing MRI maximum axial dimension (OR 1.10, p=0.0123) and a history of previous whole brain radiation therapy (OR 3.48, p=0.0243). Receipt of stereotactic radiosurgery with concurrent immunotherapy was associated with a decreased risk of local failure (HR 0.31, p=0.0159). Time interval between diagnostic MRI and first treatment, time interval between CT simulation and first treatment, and concurrent immunotherapy had no impact on incidence of radionecrosis or regional failure. DISCUSSION/UNASSIGNED:An optimal time interval between diagnosis and treatment for intact brain metastases that minimizes radionecrosis and maximizes local and regional control could not be identified. Concurrent immunotherapy does not appear to increase the risk of radionecrosis and may improve local control. These data further support the safety and synergistic efficacy of stereotactic radiosurgery with concurrent immunotherapy.

GABAergic inhibitory neurons are the principal source of inhibition in the brain. Traditionally, their role in maintaining the balance of excitation-inhibition has been emphasized. Beyond homeostatic functions, recent circuit mapping and functional manipulation studies have revealed a wide range of specific roles that GABAergic circuits play in dynamically tilting excitation-inhibition coupling across spatio-temporal scales. These span from gating of compartment- and input-specific signaling, gain modulation, shaping input-output functions and synaptic plasticity, to generating signal-to-noise contrast, defining temporal windows for integration and rate codes, as well as organizing neural assemblies, and coordinating inter-regional synchrony. GABAergic circuits are thus instrumental in controlling single-neuron computations and behaviorally-linked network activity. The activity dependent modulation of sensory and mnemonic information processing by GABAergic circuits is pivotal for the formation and maintenance of episodic memories in the hippocampus. Here, we present an overview of the local and long-range GABAergic circuits that modulate the dynamics of excitation-inhibition and disinhibition in the main output area of the hippocampus CA1, which is crucial for episodic memory. Specifically, we link recent findings pertaining to GABAergic neuron molecular markers, electrophysiological properties, and synaptic wiring with their function at the circuit level. Lastly, given that area CA1 is particularly impaired during early stages of Alzheimer's disease, we emphasize how these GABAergic circuits may contribute to and be involved in the pathophysiology.

INTRODUCTION/UNASSIGNED:Extracting regularities from ongoing stimulus streams to form predictions is crucial for adaptive behavior. Such regularities exist in terms of the content of the stimuli and their timing, both of which are known to interactively modulate sensory processing. In real-world stimulus streams such as music, regularities can occur at multiple levels, both in terms of contents (e.g., predictions relating to individual notes vs. their more complex groups) and timing (e.g., pertaining to timing between intervals vs. the overall beat of a musical phrase). However, it is unknown whether the brain integrates predictions in a manner that is mutually congruent (e.g., if "beat" timing predictions selectively interact with "what" predictions falling on pulses which define the beat), and whether integrating predictions in different timing conditions relies on dissociable neural correlates. METHODS/UNASSIGNED:= 20) performing a repetition detection task. RESULTS/UNASSIGNED:Our results reveal that temporal predictions based on beat or interval timing modulated mismatch responses to violations of "what" predictions happening at the predicted time points, and that these modulations were shared between types of temporal predictions in terms of the spatiotemporal distribution of EEG signals. Effective connectivity analysis using dynamic causal modeling showed that the integration of "what" and "when" predictions selectively increased connectivity at relatively late cortical processing stages, between the superior temporal gyrus and the fronto-parietal network. DISCUSSION/UNASSIGNED:Taken together, these results suggest that the brain integrates different predictions with a high degree of mutual congruence, but in a shared and distributed cortical network. This finding contrasts with recent studies indicating separable mechanisms for beat-based and memory-based predictive processing.

[This corrects the article DOI: 10.3389/fonc.2023.1132777.].

INTRODUCTION/UNASSIGNED:Alzheimer's disease (AD) and epilepsy are reciprocally related. Among sporadic AD patients, clinical seizures occur in 10-22% and subclinical epileptiform abnormalities occur in 22-54%. Cognitive deficits, especially short-term memory impairments, occur in most epilepsy patients. Common neurophysiological and molecular mechanisms occur in AD and epilepsy. The choroid plexus undergoes pathological changes in aging, AD, and epilepsy, including decreased CSF turnover, amyloid beta (Aβ), and tau accumulation due to impaired clearance and disrupted CSF amino acid homeostasis. This pathology may contribute to synaptic dysfunction in AD and epilepsy. METHODS/UNASSIGNED:= 12) using laser capture microdissection (LCM) followed by label-free quantitative mass spectrometry on the choroid plexus adjacent to the hippocampus at the lateral geniculate nucleus level. RESULTS/UNASSIGNED: DISCUSSION/UNASSIGNED:We found altered signaling pathways in the choroid plexus of severe AD cases and many correlated changes in the protein expression of cell metabolism pathways in AD and epilepsy cases. The shared molecular mechanisms should be investigated further to distinguish primary pathogenic changes from the secondary ones. These mechanisms could inform novel therapeutic strategies to prevent disease progression or restore normal function. A focus on dual-diagnosed AD/epilepsy cases, specific epilepsy syndromes, such as temporal lobe epilepsy, and changes across different severity levels in AD and epilepsy would add to our understanding.