ABSTRACT
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.
Subject(s)
Cognitive Dysfunction/diagnosis , Magnetic Resonance Imaging/methods , Multiple Sclerosis/complications , Neuropsychological Tests/standards , Aged, 80 and over , Diagnosis, Differential , Female , Humans , Multiple Sclerosis/psychologyABSTRACT
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 Aß 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 Aß neurotoxicity. Pharmacological readout translates into both first exposure (pâ¯=â¯0.037) and disease modifying effect (pâ¯=â¯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.
Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/therapy , Cholinergic Neurons/metabolism , Recombinant Fusion Proteins , alpha7 Nicotinic Acetylcholine Receptor/genetics , Alleles , Alzheimer Disease/diagnosis , Alzheimer Disease/etiology , Amyloid beta-Peptides/metabolism , Biomarkers , Cell Line , Cholinergic Antagonists/pharmacology , Cholinergic Antagonists/therapeutic use , Drug Evaluation, Preclinical , Fluorescent Antibody Technique , Gene Dosage , Gene Frequency , Genotype , Humans , Induced Pluripotent Stem Cells/metabolism , Phenotype , Synaptic Transmission , Translational Research, Biomedical , Treatment Outcome , alpha7 Nicotinic Acetylcholine Receptor/metabolismABSTRACT
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 (Aß1-42) 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 Aß1-42 uptake suggesting a protective effect beyond physiological concentrations. Furthermore, in the presence of CHRFAM7A Aß1-42 uptake activated neuronal interleukin 1ß (IL-1ß) 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.
