Citations

Fibrolamellar hepatocellular carcinoma (FLC) is a usually lethal primary liver cancer driven by a somatic dysregulation of protein kinase A. We show that the proteome of FLC tumors is distinct from that of adjacent nontransformed tissue. These changes can account for some of the cell biological and pathological alterations in FLC cells, including their drug sensitivity and glycolysis. Hyperammonemic encephalopathy is a recurrent problem in these patients, and established treatments based on the assumption of liver failure are unsuccessful. We show that many of the enzymes that produce ammonia are increased and those that consume ammonia are decreased. We also demonstrate that the metabolites of these enzymes change as expected. Thus, hyperammonemic encephalopathy in FLC may require alternative therapeutics.

AbstractBackgroundThe Longitudinal Early‐onset Alzheimer Disease study (LEADS) aims to robustly characterize biomarkers of early‐onset AD (EOAD). Here we quantified white matter hyperintensities (WMH) in EOAD and compared the volume of WMH with that of cognitively normal (CN) and amyloid‐negative early‐onset dementia (EOnonAD) groups.MethodsWe compared WMH of 194 amyloid‐positive EOAD, 59 amyloid‐negative EOnonAD, and 88 cognitively normal participants. WMH in left and right frontal, temporal, parietal, and occipital regions was compared between the group, as well as the sum total in each hemisphere. For distributional considerations, the logarithm of the WMHs was used in the analyses. Group comparisons were performed using t‐tests. Analyses of variance were used to compare the groups after correcting for the effects of age, sex, and education. Linear regression analyses were used to investigate the association between cognitive impairment and WMH using age, sex, and education as covariates. Cognitive impairment was measured using the Mini‐Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) scale sum of boxes (CDR‐sb). All p‐values were corrected for multiple comparisons using the false discovery rate method.ResultsEOAD showed greater WMH compared with both CN and EOnonAD groups across all regions. This relationship holds after correcting for the effects of age, sex, and education (see Figure 1 and Table 1, all p‐values < 0.05). No significant differences were observed between WMHs of CN and EOnonAD groups. Higher WMH values were associated with greater cognitive impairment: MMSE (b = ‐1.69, p‐value <0.0001) and CDR‐sb (b = 0.45, p‐value <0.0001).ConclusionsEOAD consistently show higher WMH compared to their CN and EOnonAD peers. The extent of WMH in CN and EOnonAD groups is similar. No differences in regional distribution were observed, with EOAD having higher WMH across all brain regions. Higher WMHs were associated with worse cognitive impairment measured both using MMSE and CDR sum of boxes.

AbstractBackgroundThe semantic fluency task involves naming as many items as possible in a given category (e.g., animals) in one minute. It is often interpreted as a measure of word retrieval, but also draws on executive function abilities to organize responses and develop task‐specific strategies. Indeed, both language skills and dementia severity ratings have recently been found to correlate with semantic fluency performance in patients with primary progressive aphasia (Riello et al., 2022; Scheffel et al., 2021). Here, we focused instead on how performance on language and executive function measures predicts longitudinal change in semantic fluency performance in patients with progressive agrammatic aphasia and/or apraxia of speech (AOS).MethodPatients with isolated agrammatic aphasia (n = 10), isolated AOS (n = 42), or a combination of the two (n = 59) with 1‐7 visits (mean = 2.19) were included. We used Bayesian hierarchical linear models to investigate whether baseline measures of executive function or language were associated with the rate at which semantic fluency performance changes over time while accounting for baseline diagnosis group, sex, education, age at baseline, and baseline disease duration.ResultSemantic fluency performance declined over time, at a similar rate irrespective of diagnostic group (isolated or combined aphasia or AOS; Figure 1). Across all patients, higher executive function abilities at baseline, as indicated by faster Trails Making Test B completion times, predicted higher baseline semantic fluency performance and also a steeper annual rate of decline (Figure 2). Similarly, higher fluency ratings during the Western Aphasia Battery‐Revised picture description at baseline were associated with higher baseline semantic fluency performance and faster decline. Baseline performance on the Boston Naming Test and Token Test were also associated with baseline semantic fluency, but not with longitudinal change.ConclusionThese results better delineate how language and executive function abilities support performance in the semantic fluency task. Higher abilities in those areas at baseline do not appear to be protective over time. Rather, the differences in semantic fluency that are present at baseline disappear as the disease progresses.

AbstractBackgroundThe ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study is designed to characterize both sporadic and familial FTLD (f‐FTLD) through annual detailed clinical, neuropsychological, biomarker, and neuroimaging assessments to capture disease onset and trajectory in preparation for therapeutic trails in FTLD. Transitions from asymptomatic to mild disease, or from mild to overt, may reveal critical windows for intervention.Method169 f‐FTLD participants carrying mutations in the main FTLD‐associated genes (79 C9orf72; 37 GRN; 53 MAPT) with at least two clinical assessments were included for analysis of phenoconversion from asymptomatic or mild disease. [CDRÒ + NACC FTLD global scores (Miyagawa et al, 2020) were used to define baseline status at first visit: “asymptomatic” = 0 and “mild” = 0.5. Conversion was defined as “partial” (asymptomatic to mild), “definite” (asymptomatic to overt [CDRÒ + NACC FTLD > = 1) and “mild to overt” (0.5 to > = 1).ResultDefinite conversion occurred most often in MAPT mutation carriers, with 5/43 asymptomatic carriers transitioning through mild to overt across multiple visits. Definite conversion was also seen in 2/65 C9orf72 expansion carriers and 1/30 GRN mutation carriers. All definite converters were assessed as mild (CDRÒ + NACC FTLD = 0.5) for at least one intermediate visit; definite conversion was observed from 2‐4 years from initial assessment. Partial conversions also occurred in all three genetic groups (MAPT: 6; C9orf72: 5; GRN: 5). Further conversion is expected to be observed in these participants in additional follow‐up visits. C9orf72 expansion carriers were less likely to progress from a baseline of mild to overt (3/14) than GRN carriers (4/6) or MAPT (7/10).ConclusionLongitudinal assessment through natural history studies can capture early phenoconversion in carriers of FTLD‐associated genetic mutations; corresponding imaging, cognitive, and biomarker profiles captured may provide insights into disease mechanisms and trajectories.

Abstract Objective Previous studies suggested that patients with epilepsy might be able to forecast their own seizures. This study aimed to assess the relationships between premonitory symptoms, perceived seizure risk, and future and recent self‐reported and electroencephalographically (EEG)‐confirmed seizures in ambulatory patients with epilepsy in their natural home environments. Methods Long‐term e‐surveys were collected from patients with and without concurrent EEG recordings. Information obtained from the e‐surveys included medication adherence, sleep quality, mood, stress, perceived seizure risk, and seizure occurrences preceding the survey. EEG seizures were identified. Univariate and multivariate generalized linear mixed‐effect regression models were used to estimate odds ratios (ORs) for the assessment of the relationships. Results were compared with the seizure forecasting classifiers and device forecasting literature using a mathematical formula converting OR to equivalent area under the curve (AUC). Results Fifty‐four subjects returned 10 269 e‐survey entries, with four subjects acquiring concurrent EEG recordings. Univariate analysis revealed that increased stress (OR = 2.01, 95% confidence interval [CI] = 1.12–3.61, AUC = .61, p = .02) was associated with increased relative odds of future self‐reported seizures. Multivariate analysis showed that previous self‐reported seizures (OR = 5.37, 95% CI = 3.53–8.16, AUC = .76, p < .001) were most strongly associated with future self‐reported seizures, and high perceived seizure risk (OR = 3.34, 95% CI = 1.87–5.95, AUC = .69, p < .001) remained significant when prior self‐reported seizures were added to the model. No correlation with medication adherence was found. No significant association was found between e‐survey responses and subsequent EEG seizures. Significance Our results suggest that patients may tend to self‐forecast seizures that occur in sequential groupings and that low mood and increased stress may be the result of previous seizures rather than independent premonitory symptoms. Patients in the small cohort with concurrent EEG showed no ability to self‐predict EEG seizures. The conversion from OR to AUC values facilitates direct comparison of performance between survey and device studies involving survey premonition and forecasting.

AbstractIntroductionWe examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early‐onset Alzheimer's disease (EOAD; onset 40‐64 years) at the midway point of data collection for the Longitudinal Early‐onset Alzheimer's Disease Study (LEADS).MethodsBaseline NPS (Neuropsychiatric Inventory – Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups – amyloid‐positive EOAD (n = 212) and amyloid negative early‐onset non‐Alzheimer's disease (EOnonAD; n = 70).ResultsAffective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD.DiscussionOverall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late‐onset AD.

Abstract Background Antimicrobial resistance (AMR) is undermining modern medicine, a problem compounded by bacterial adaptation to antibiotic pressures. Phages are viruses that infect bacteria. Their diversity and evolvability offer the prospect of their use as a therapeutic solution. Reported are outcomes of customized phage therapy for patients with difficult-to-treat antimicrobial resistant infections. Methods We retrospectively assessed 12 cases of customized phage therapy from a phage production center. Phages were screened, purified, sequenced, characterized, and Food and Drug Administration–approved via the IND (investigational new drug) compassionate-care route. Outcomes were assessed as favorable or unfavorable by microbiologic and clinical standards. Infections were device-related or systemic. Other experiences such as time to treatment, antibiotic synergy, and immune responses were recorded. Results Fifty requests for phage therapy were received. Customized phages were generated for 12 patients. After treatment, 42% (5/12) of cases showed bacterial eradication and 58% (7/12) showed clinical improvement, with two-thirds of all cases (66%) showing favorable responses. No major adverse reactions were observed. Antibiotic-phage synergy in vitro was observed in most cases. Immunological neutralization of phages was reported in 5 cases. Several cases were complicated by secondary infections. Complete characterization of the phages (morphology, genomics, and activity) and their production (methods, sterility, and endotoxin tests) are reported. Conclusions Customized phage production and therapy was safe and yielded favorable clinical or microbiological outcomes in two-thirds of cases. A center or pipeline dedicated to tailoring the phages against a patient's specific AMR bacterial infection may be a viable option where standard treatment has failed.

AbstractObjectiveThe Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early‐onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data‐collection mid‐point.MethodsData from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid‐positive EOAD [n = 212], and amyloid‐negative early‐onset non‐Alzheimer's disease [EOnonAD; n = 70]).ResultsCognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures.ConclusionsWe present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant.HIGHLIGHTS Findings represent the most comprehensive baseline characterization of sporadic early‐onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present.

AbstractOBJECTIVEInvestigation of learning slopes in early‐onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early‐onset dementia with and without β‐amyloid positivityMETHODData from 310 participants in the Longitudinal Early‐Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determinedRESULTSWorse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric—the learning ratio (LR)—outperformed other learning slope calculations across analysesCONCLUSIONSLearning slopes appear to be sensitive to early‐onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses.Highlights Learning is impaired in amyloid‐positive EOAD, beyond cognitive severity scores alone. Amyloid‐positive EOAD participants perform worse on learning slopes than amyloid‐negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants.