Background Cholinergic neuronal loss is one of the hallmarks of AD related neurodegeneration; however, preclinical promise of α7 nAChR drugs failed to translate into humans. CHRFAM7A , a uniquely human fusion gene, is a negative regulator of α7 nAChR and was unaccounted for in preclinical models. Methods Molecular methods: Function of CHRFAM7A alleles was studied in vitro in two disease relevant phenotypic readouts: electrophysiology and Aβ uptake. Genome edited human induced pluripotent stem cells (iPSC) were used as a model system with the human context. Double blind pharmacogenetic study: We performed double-blind pharmacogenetic analysis on the effect of AChEI therapy based on CHRFAM7A carrier status in two paradigms: response to drug initiation and DMT effect. Mini Mental Status Examination (MMSE) was used as outcome measure. Change in MMSE score from baseline was compared by 2-tailed T-test. Longitudinal analysis of clinical outcome (MMSE) was performed using a fitted general linear model, based on an assumed autoregressive covariance structure. Model independent variables included age, sex, and medication regimen at the time of the first utilized outcome measure (AChEI alone or AChEI plus memantine), APOE4 carrier status (0, 1 or 2 alleles as categorical variables) and CHRFAM7A genotype. Findings The direct and inverted alleles have distinct phenotypes. Functional CHRFAM7A allele classifies the population as 25% non-carriers and 75% carriers. Induced pluripotent stem cell (iPSC) models α7 nAChR mediated Aβ neurotoxicity. Pharmacological readout translates into both first exposure ( p = 0.037) and disease modifying effect ( p = 0.0048) in two double blind pharmacogenetic studies. Interpretation CHRFAM7A accounts for the translational gap in cholinergic strategies in AD. Clinical trials not accounting for this uniquely human genetic factor may have rejected drug candidates that would benefit 25% of AD. Reanalyses of the completed trials using this pharmacogenetic paradigm may identify effective therapy. Funding:
The α7 nicotinic acetylcholine receptor (α7nAChR) has been a promising target for diseases affecting cognition and higher cortical functions; however, the effect observed in animal models failed to translate into human clinical trials identifying a translational gap. CHRFAM7A is a human-specific fusion gene with properties that enable incorporation into the α7nAChR and, being human specific, CHRFAM7A effect was not accounted for in preclinical studies. We hypothesized that CHRFAM7A may account for this translational gap and understanding its function may offer novel insights when exploring α7nAChR as a drug target. CHRFAM7A is present in different copy number variations (CNV) in the human genome with high frequency. To study the functional consequences of the presence of the CHRFAM7A, two induced pluripotent stem cell (iPSC) lines (0 copy and 1 copy direct) were developed. The 0 copy line was rescued with CHRFAM7A transfection to control for genetic heterogeneity. As readouts for genotype–phenotype correlation, α7nAChR synaptic transmission and amyloid beta 1–42 (Aβ1–42) uptake were tested. Synaptic transmission in the presence of CHRFAM7A demonstrated that PNU-modulated desensitization of α7nAChR currents increased as a function of CHRFAM7A dosage. CHRFAM7A mitigated the dose response of Aβ1–42 uptake suggesting a protective effect beyond physiological concentrations. Furthermore, in the presence of CHRFAM7A Aβ1–42 uptake activated neuronal interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) without activating the canonical inflammasome pathway. Lead optimization may identify more potent molecules when the screen has a model harboring CHRFAM7A. Incorporating pharmacogenetics into clinical trials may enhance signals in efficacy measures.
Due to increasingly improved disability outcomes, and the resultant significantly improved life span, of the multiple sclerosis (MS) population, questions regarding cognitive aging and the prevalence of comorbid Alzheimer disease (AD) have emerged. We describe neuropsychological and MRI-based changes that occurred in an 84-year-old MS patient with comorbid amnestic mild cognitive impairment (a precursor to AD) and cerebrovascular pathology. The neuropsychological examination demonstrated impairment in cognitive processing speed as well as in verbal and visual memory—domains that are potentially affected by any, or all, of the three co-existing diseases. Amyloid-based PET imaging showed increased focal uptake within the gray matter of the occipital lobe. We highlight how these clinical and radiologic observations can inform future research that could elucidate interactions between MS, a probable AD diagnosis, and cerebrovascular pathology in elderly individuals with MS. A comprehensive neuropsychological examination of multiple cognitive domains of individuals with MS may aid in the differential diagnosis of late-in-life cognitive decline.
Materials and Methods We reviewed mechanical thrombectomy cases performed at University of Pittsburgh Medical Center's (UPMC) Presbyterian and Mercy hospitals between February 2018 and August 2019, identifying those meeting criteria under capitation models negotiated with Companies A, B, and C (table 1). We calculated the cost of equipment for each thrombectomy using the negotiated cost for individual devices utilized and compared this sum to the total derived from cost-negotiated bundled equipment packages, resulting in the difference between non-capitated and capitated cost. Results 107 cases were identified as meeting the criteria for capitation under the negotiated contracts; 39 cases using Company A (28 using stentrievers), 44 cases using Company B (3 using stentrievers), and 24 cases using Company C (14 using stentrievers).
Background: 30% of minor stroke symptom (MSS) patients (NIHSS=<5) have underlying large vessel occlusions (LVO). MSS patients are less likely to receive endovascular therapy (EVT) and thrombolytic therapy. 20-25% of patients with LVO suffer early neurological deterioration (END), ≥ 4 points decrease on NIHSS, which is associated with worse outcomes. The predictability of END is currently unclear and there is need for elucidation on the factors which precipitate rapid decline. Methods: Retrospective review of MSS-LVO patients across two multi-hospital centers from June 2015 thru June 2018 was conducted. Patients who underwent immediate EVT without signs of deterioration were excluded. Baseline characteristics, management, and outcomes were compared with t-tests, Mann-Whitney U, Chi-square, Fisher’s exact test, and Fisher-Freeman-Halton test for continuous and categorical variables, as appropriate using SPSS Software. Results: Of the 45 MSS-LVO patients who were included, 12 suffered END. Demographics and baseline characteristics were not significantly different across groups. Weakness was more often a presenting symptom in the No-END cohort (84.8% vs 41.7% in END group, p=0.01). The END group showed a lower diastolic BP at the time of the highest NIHSS (86mmHg vs 72mmHg in END group, p= 0.03). The highest BP was comparable across groups (180/84 in the No END group vs 182/91 in END group, p>0.05); although in the END group, the high BP correlated with a higher NIHSS (3 vs 0 in No END group, p=0.01). Patients in the END group were more likely to receive tpA (58.3% vs 15.2% in No END group, p=0.01). The 24-hour NIHSS was greater in the END group (2.5 vs. 0, p=0.02). 84.4% of patients in the No END group had good functional outcome at 3-5 days (mRS 0-2), compared to 45.5% of the END patients (p=0.02). 25% of the END group had in-hospital mortality, while there were no deaths in the No END group. Fewer patients were discharged home (72.7% in No END vs 58.3% in END group, p=0.04). Conclusion: END in MSS patients is associated with worse outcomes at 3-5 days and higher in-hospital mortality. Presenting symptoms and BP fluctuations may be factors in predicting END. Further studies are needed to elucidate the risk factors associated with END in MSS-LVO patients.
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