Faculty Bibliography

INTRODUCTION/BACKGROUND:Mild to moderate exercise may decrease Alzheimer's disease (AD) risk, but the effects of vigorous, regular physical exercise remain unclear. METHODS:Two patients with initial diagnoses of amnestic mild cognitive impairment (MCI) demonstrated positive AD biomarkers throughout 16 and 8 years of follow-up, with final diagnoses of mild AD and amnestic MCI, respectively. RESULTS:Patient 1 was diagnosed with amnestic MCI at age 64. Neuropsychological testing, magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET), amyloid imaging PET, and cerebrospinal fluid (CSF) biomarkers during follow-ups remained consistent with AD. By age 80, progression was minimal with Montreal Cognitive Assessment (MoCA) 26 of 30. Patient 2 was diagnosed with amnestic MCI at age 72. Neuropsychological testing, MRI, FDG-PET, and amyloid imaging PET during follow-ups remained consistent with AD. At age 80, MoCA was 27 of 30 with no clinical progression. Both patients regularly performed vigorous, regular exercise that increased after retirement/work reduction. DISCUSSION/CONCLUSIONS:Vigorous, regular exercise may slow disease progression in biomarker-positive amnestic MCI and mild AD.

OBJECTIVE:High-fat and low-carbohydrate diets can reduce seizure frequency in some treatment-resistant epilepsy patients, including the more flexible modified Atkins diet (MAD), which is more palatable, mimicking fasting and inducing high ketone body levels. Low-carbohydrate diets may shift brain energy production, particularly impacting neuron- and astrocyte-linked metabolism. METHODS:We evaluated the effect of short-term MAD on molecular mechanisms in adult epilepsy patients from surgical brain tissue and plasma compared to control participants consuming a nonmodified higher carbohydrate diet (n = 6 MAD, mean age = 43.7 years, range = 21-53, diet for average 10 days; n = 10 control, mean age = 41.9 years, range = 28-64). RESULTS: = .48). Brain proteomics and RNAseq identified few differences, including 2.75-fold increased hippocampal MT-ND3 and trends (p < .01, false discovery rate > 5%) in hippocampal nicotinamide adenine dinucleotide (NADH)-related signaling pathways (activated oxidative phosphorylation and inhibited sirtuin signaling). SIGNIFICANCE/CONCLUSIONS:Short-term MAD was associated with metabolic differences in plasma and resected epilepsy brain tissue when compared to control participants, in combination with trending expression changes observed in hippocampal NADH-related signaling pathways. Future studies should evaluate how brain molecular mechanisms are altered with long-term MAD in a larger cohort of epilepsy patients, with correlations to seizure frequency, epilepsy syndrome, and other clinical variables. [Clinicaltrials.gov NCT02565966.].

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

OBJECTIVE:Identify molecular mechanisms in brain tissue of Rasmussen encephalitis (RE) when compared to people with non-RE epilepsy (PWE) and control cases using whole exome sequencing (WES), RNAseq, and proteomics. METHODS:Frozen brain tissue (ages 2-19 years) was obtained from control autopsy (n=14), surgical PWE (n=10), and surgical RE cases (n=27). We evaluated WES variants in RE associated with epilepsy, seizures, RE, and human leukocyte antigens (HLAs). Differential expression was evaluated by RNAseq (adjusted p<0.05) and label-free quantitative mass spectrometry (false discovery rate<5%) in the three groups. RESULTS:, z=5.61). Proteomics detected fewer altered targets. SIGNIFICANCE/CONCLUSIONS:In RE, we identified activated immune signaling pathways and immune cell type annotation enrichment that suggest roles of the innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE. Follow up studies could evaluate cell type density and subregional localization associated with top targets, clinical history (neuropathology, disease duration), and whether modulating crosstalk between dendritic and natural killer cells may limit disease progression.

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.

Phosphorylated tau is the main protein present in neurofibrillary tangles, the presence of which is a key neuropathological hallmark of Alzheimer's disease (AD). The toxic effects of phosphorylated tau are likely mediated by interacting proteins; however, methods to identify these interacting proteins comprehensively in human brain tissue are limited. Here, we describe a method that enables the efficient identification of hundreds of proteins that interact with phosphorylated tau (pTau), using affinity purification-mass spectrometry (AP-MS) on human, fresh-frozen brain tissue from donors with AD. Tissue is homogenized using a gentle technique that preserves protein-protein interactions, and co-immunoprecipitation of pTau and its interacting proteins is performed using the PHF1 antibody. The resulting protein interactors are then identified using label-free quantitative liquid chromatography-mass spectrometry (LC-MS)/MS. The Significance Analysis of INTeractome (SAINT) algorithm is used to determine which proteins significantly interact with pTau. This approach enables the detection of an abundance of all 6 isoforms of tau, 23 phosphorylated residues on tau, and 125 significant pTau protein interactors, in human AD brain tissue.

Alzheimer's disease (AD) is the most common cause of age-associated dementia and will exponentially rise in prevalence in the coming decades, supporting the parallel development of the early stage detection and disease-modifying strategies. While primarily considered as a cognitive disorder, AD also features motor symptoms, primarily gait dysfunction. Such gait abnormalities can be phenotyped across classic clinical syndromes as well as by quantitative kinematic assessments to address subtle dysfunction at preclinical and prodromal stages. As such, certain measures of gait can predict the future cognitive and functional decline. Moreover, cross-sectional and longitudinal studies have associated gait abnormalities with imaging, biofluid, and genetic markers of AD across all stages. This suggests that gait assessment is an important tool in the clinical assessment of patients across the AD spectrum, especially to help identify at-risk individuals.

BACKGROUND:Limited data exists evaluating predictors of long-term outcomes after hospitalization for COVID-19. METHODS:We conducted a prospective, longitudinal cohort study of patients hospitalized for COVID-19. The following outcomes were collected at 6 and 12-months post-diagnosis: disability using the modified Rankin Scale (mRS), activities of daily living assessed with the Barthel Index, cognition assessed with the telephone Montreal Cognitive Assessment (t-MoCA), Neuro-QoL batteries for anxiety, depression, fatigue and sleep, and post-acute symptoms of COVID-19. Predictors of these outcomes, including demographics, pre-COVID-19 comorbidities, index COVID-19 hospitalization metrics, and life stressors, were evaluated using multivariable logistic regression. RESULTS:Of 790 COVID-19 patients who survived hospitalization, 451(57%) completed 6-month (N = 383) and/or 12-month (N = 242) follow-up, and 77/451 (17%) died between discharge and 12-month follow-up. Significant life stressors were reported in 121/239 (51%) at 12-months. In multivariable analyses, life stressors including financial insecurity, food insecurity, death of a close contact and new disability were the strongest independent predictors of worse mRS, Barthel Index, depression, fatigue, and sleep scores, and prolonged symptoms, with adjusted odds ratios ranging from 2.5 to 20.8. Other predictors of poor outcome included older age (associated with worse mRS, Barthel, t-MoCA, depression scores), baseline disability (associated with worse mRS, fatigue, Barthel scores), female sex (associated with worse Barthel, anxiety scores) and index COVID-19 severity (associated with worse Barthel index, prolonged symptoms). CONCLUSIONS:Life stressors contribute substantially to worse functional, cognitive and neuropsychiatric outcomes 12-months after COVID-19 hospitalization. Other predictors of poor outcome include older age, female sex, baseline disability and severity of index COVID-19.

Background: White matter hyperintensities (WMHs) are observed frequently on MRI in elderly and associated with cognitive dysfunction. Many studies focused on intracranial small vessel disease (SVD), however, few studies linked WMHs with changes of extracranial large feeding arteries. We aimed to investigate the effects of internal carotid artery (ICA) tortuosity changes through quantitative MR Angiography. Method: Fifty-seven patients (age: 72.98±5.62; 32 females/25 males) with WMHs were included. WMHs lesions were semi-automatically segmented on FLAIR images. ICAs were segmented on the TOF images to generate tortuosity quantitative metrics, including tortuosity index (TI), inflection count metric (ICM), and ICA angle (Figure 1). According to the Fazekas scores, patients were categorized into mild, moderate and severe groups as summarized in Table 1. One-way ANOVA analyses were applied to reveal the difference of averaged bilateral ICAs' tortuosity measurements. Pearson's correlation coefficients were calculated to quantitatively investigate the relationship between tortuosity and volumes of lesions that are apart from the ventricle in subcortical white matter, i.e., deep white matter lesions (DWMLs), as well as the lesions attached with the ventricular system, i.e., periventricular white matter lesions (PVWMLs). Result: Patients with higher Fazekas scores have higher TI and ICM, indicating higher tortuosity (Figure 2). The correlation results showed that TI and ICM were positively correlated with DWMLs volumes (r = 0.33, P< 0.05; r = 0.4, P< 0.01), however, they did not show associations with PVWMLs. While there's no correlation between averaged bilateral ICA angles and DWMLs or PVWMLs, we found significant correlations between left ICA angles and DWML volumes on left brain (r =0.56, P < 0.005) as well as between right ICA angles and DWML volumes on right brain (r = 0.49, P < 0.05) (Figure 3). Conclusion: Tortuosity measurements derived from TOF images showed that subjects with higher degree of ICA tortuosity had higher lesion volumes of DWMLs not PVWMLs, indicating DWMLs may have different etiologies such as ischemic origin. The findings also highlight the importance of ICA angle as a risk factor for WMHs development which might be associated with the local hemodynamic shear stress at the bulb, where the ICA plaques are often developed.