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Background: Human restricted genes contribute to human specific traits in the immune system. CHRFAM7A, a uniquely human fusion gene, is a negative regulator of the α7 nicotinic acetylcholine receptor (α7 nAChR), the highest Ca 2+ conductor of the ACh receptors implicated in innate immunity. Understanding the mechanism of how CHRFAM7A affects the immune system remains unexplored., Methods: Two model systems are used, human induced pluripotent stem cells (iPSC) and human primary monocytes, to characterize α7 nAChR function, Ca 2+ dynamics and decoders to elucidate the pathway from receptor to phenotype., Findings: CHRFAM7A/α7 nAChR is identified as a hypomorphic receptor with mitigated Ca 2+ influx and prolonged channel closed state. This shifts the Ca 2+ reservoir from the extracellular space to the endoplasmic reticulum (ER) leading to Ca 2+ dynamic changes. Ca 2+ decoder small GTPase Rac1 is then activated, reorganizing the actin cytoskeleton. Observed actin mediated phenotypes include cellular adhesion, motility, phagocytosis and tissue mechanosensation., Interpretation: CHRFAM7A introduces an additional, human specific, layer to Ca 2+ regulation leading to an innate immune gain of function. Through the actin cytoskeleton it drives adaptation to the mechanical properties of the tissue environment leading to an ability to invade previously immune restricted niches. Human genetic diversity predicts profound translational significance as its understanding builds the foundation for successful treatments for infectious diseases, sepsis, and cancer metastasis., Funding: This work is supported in part by the Community Foundation for Greater Buffalo (Kinga Szigeti) and in part by NIH grant R01HL163168 (Yongho Bae)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: CHRFAM7A , a uniquely human fusion gene, has been associated with neuropsychiatric disorders including Alzheimer's disease, schizophrenia, anxiety, and attention deficit disorder. Understanding the physiological function of CHRFAM7A in the human brain is the first step to uncovering its role in disease. CHRFAM7A was identified as a potent modulator of intracellular calcium and an upstream regulator of Rac1 leading to actin cytoskeleton reorganization and a switch from filopodia to lamellipodia implicating a more efficient neuronal structure. We performed a neurocognitive-MRI correlation exploratory study on 46 normal human subjects to explore the effect of CHRFAM7A on human brain., Methods: Dual locus specific genotyping of CHRFAM7A was performed on genomic DNA to determine copy number (TaqMan assay) and orientation (capillary sequencing) of the CHRFAM7A alleles. As only the direct allele is expressed at the protein level and affects α7 nAChR function, direct allele carriers and non-carriers are compared for neuropsychological and MRI measures. Subjects underwent neuropsychological testing to measure motor (Timed 25-foot walk test, 9-hole peg test), cognitive processing speed (Symbol Digit Modalities Test), Learning and memory (California Verbal Learning Test immediate and delayed recall, Brief Visuospatial Memory Test-Revised immediate and delayed recall) and Beck Depression Inventory-Fast Screen, Fatigue Severity Scale. All subjects underwent MRI scanning on the same 3 T GE scanner using the same protocol. Global and tissue-specific volumes were determined using validated cross-sectional algorithms including FSL's Structural Image Evaluation, using Normalization, of Atrophy (SIENAX) and FSL's Integrated Registration and Segmentation Tool (FIRST) on lesion-inpainted images. The cognitive tests were age and years of education-adjusted using analysis of covariance (ANCOVA). Age-adjusted analysis of covariance (ANCOVA) was performed on the MRI data., Results: CHRFAM7A direct allele carrier and non-carrier groups included 33 and 13 individuals, respectively. Demographic variables (age and years of education) were comparable. CHRFAM7A direct allele carriers demonstrated an upward shift in cognitive performance including cognitive processing speed, learning and memory, reaching statistical significance in visual immediate recall (FDR corrected p  = 0.018). The shift in cognitive performance was associated with smaller whole brain volume (uncorrected p  = 0.046) and lower connectivity by resting state functional MRI in the visual network (FDR corrected p  = 0.027) accentuating the cognitive findings., Conclusion: These data suggest that direct allele carriers harbor a more efficient brain consistent with the cellular biology of actin cytoskeleton and synaptic gain of function. Further larger human studies of cognitive measures correlated with MRI and functional imaging are needed to decipher the impact of CHRFAM7A on brain function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Jakimovski, Dorn, Regno, Bartnik, Bergsland, Ramanathan, Dwyer, Benedict, Zivadinov and Szigeti.)

Genes restricted to humans may contribute to human-specific traits and provide a different context for diseases. CHRFAM7A is a uniquely human fusion gene and a negative regulator of the α7 nicotinic acetylcholine receptor (α7 nAChR). The α7 nAChR has been a promising target for diseases affecting cognition and higher cortical functions, however, the treatment effect observed in animal models failed to translate into human clinical trials. As CHRFAM7A was not accounted for in preclinical drug screens it may have contributed to the translational gap. Understanding the complex genetic architecture of the locus, deciphering the functional impact of CHRFAM7A on α7 nAChR neurobiology and utilizing human-relevant models may offer novel approaches to explore α7 nAChR as a drug target., (© 2024. The Author(s).)

Background: While advancements in imaging techniques have led to major strides in deciphering the human brain, successful interventions are elusive and represent some of the most persistent translational gaps in medicine. Human restricted CHRFAM7A has been associated with neuropsychiatric disorders., Methods: The physiological role of CHRFAM7A in human brain is explored using multiomics approach on 600 post mortem human brain tissue samples. The emerging pathways and mechanistic hypotheses are tested and validated in an isogenic hiPSC model of CHRFAM7A knock-in medial ganglionic eminence progenitors and neurons., Findings: CHRFAM7A is identified as a modulator of intracellular calcium dynamics and an upstream regulator of Rac1. Rac1 activation re-designs the actin cytoskeleton leading to dynamic actin driven remodeling of membrane protrusion and a switch from filopodia to lamellipodia. The reinforced cytoskeleton leads to an advantage to tolerate stiffer mechanical properties of the extracellular environment., Interpretation: CHRFAM7A modifies the actin cytoskeleton to a more dynamic and stiffness resistant state in an α7nAChR dependent manner. CHRFAM7A may facilitate neuronal adaptation to changes in the brain environment in physiological and pathological conditions contributing to risk or recovery. Understanding how CHRFAM7A affects human brain requires human studies in the areas of memory formation and erasure, cognitive reserve, and neuronal plasticity., Funding: This work is supported in part by the Community Foundation for Greater Buffalo (Kinga Szigeti). Also, in part by the International Society for Neurochemistry (ISN) and The Company of Biologists (Nicolas Rosas). ROSMAP is supported by NIA grants P30AG10161, P30AG72975, R01AG15819, R01AG17917. U01AG46152, and U01AG61356., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Methods: We administered the Global Neuropsychological Assessment (GNA), an abbreviated cognitive battery, to 105 adults aged 73.0 ± 7.1 years, including 28 with probable Alzheimer's disease, 9 with amnestic mild cognitive impairment, and 68 healthy controls. We examined group differences in baseline performance, test-retest reliability, and correlations with other conventional tests., Results: Healthy adults outperformed patients on all five GNA subtests. Test-retest intraclass correlation coefficients were significant for all GNA subtests. Among patients with healthy controls, GNA Story Memory correlated best with Wechsler Memory Scale-Revised (WMS-R) Logical Memory for learning and delayed recall, GNA Digit Span correlated most highly with the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) Digit Span, GNA Perceptual Comparison correlated most highly with the Trail Making Test, and GNA Animal Naming correlated most highly with Supermarket Item Naming., Conclusions: Preliminary findings suggest that the GNA shows good test-retest validity, clear convergent and discriminant construct validity, and excellent diagnostic criterion validity for dementia and mild cognitive impairment in an American sample.

The development of Alzheimer's disease therapeutics has been challenging, with 99% of clinical trials failing to find a significant difference between drug and placebo. While the quest continues for more effective treatments, there is emerging evidence that pharmacogenetic considerations are important factors in regard to metabolism, efficacy, and toxicity of drugs. Currently, there are five US Food and Drug Administration-approved drugs for the treatment of Alzheimer's disease; three acetylcholinesterase inhibitors, memantine, and aducanumab. Introducing a limited genetic panel consisting of APOE4, CYP2D6*10, and BChE*K would optimize acetylcholinesterase inhibitor therapy, facilitate immunotherapy risk assessment, and inform an amyloid-related imaging abnormality surveillance schedule. In view of the genetic heterogeneity of Alzheimer's disease identified in genome-wide association studies, pharmacogenetics is expected to play an increasing role in mechanism-specific treatment strategies and personalized medicine., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Neuroinflammation in Alzheimer's disease (AD) has been the focus for identifying targetable pathways for drug development. The role of amyloid beta (Aβ), a prototype of damage-associated molecular patterns (DAMPs), has been implicated in triggering an inflammatory response. As alpha7 nicotinic acetylcholine receptor (α7 nAChR) binds Aβ with high affinity, α7 nAChR may play a role in Aβ-induced neuroinflammation. The conundrum of how α7 nAChR as the mediator of the cholinergic anti-inflammatory response may trigger an inflammatory response has not been resolved. CHRFAM7A , the uniquely human fusion gene between ULK4 and CHRNA7 , is a negative regulator of α7 nAChR ionotropic function. To provide the human context, isogenic induced pluripotent stem cell (iPSC) lines were developed from CHRFAM7A null and carrier individuals by genome-editing the null line using TALENs to knock-in CHRFAM7A . In iPSC-derived microglia-like cells, CHRFAM7A mitigated Aβ uptake through the α7 nAChR. Despite the lower Aβ uptake, the presence of CHRFAM7A was associated with an innate immune response that was characterized by NF-κB activation and NF-κB target transcription ( TNFA , IL6 , and IL1B ). LPS, a prototype PAMP, induced a heightened immune response in CHRFAM7A carriers. CHRFAM7A modified the dynamics of NF-κB translocation by prolonging its nuclear presence. CHRFAM7A modified the α7 nAChR metabotropic function, resulting in a human-specific innate immune response. This iPSC model provided an opportunity to elucidate the mechanism and establish high throughput screens.

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.

The current study examined factors related to fatigue in family caregivers of individuals with dementia using a cross-sectional design to collect subjective and objective data. Findings indicated that caregivers' sleep quality, difficulty falling asleep, and depression, as well as care-recipients' functionality, were associated with family caregivers' fatigue. Regression analysis indicated that only sleep quality significantly predicted caregivers' fatigue. Study findings suggest fatigue is common among family caregivers of individuals with dementia and may be related to sleep quality. The level of fatigue identified in the current study warrants further study with larger and more diverse samples. [Journal of Gerontological Nursing, 46(9), 14-18.]., (Copyright 2020, SLACK Incorporated.)

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., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) exhibits neurodegeneration driven disability progression. We compared the extent of neurodegeneration among 112 long-standing MS patients, 37 Parkinson's disease (PD) patients, 34 amnestic mild cognitive impairment (aMCI) patients, 37 Alzheimer's disease (AD) patients, and 184 healthy controls. 3T MRI volumes of whole brain (WBV), white matter (WMV), gray matter (GMV), cortical (CV), deep gray matter (DGM), and nuclei-specific volumes of thalamus, caudate, putamen, globus pallidus, and hippocampus were derived with SIENAX and FIRST software. Аge and sex-adjusted analysis of covariance was used. WBV was not significantly different between diseases. MS had significantly lower WMV compared to other disease groups (p < 0.021). Only AD had smaller GMV and CV when compared to MS (both p < 0.001). MS had smaller DGM volume than PD and aMCI (p < 0.001 and p = 0.026, respectively) and lower thalamic volume when compared to all other neurodegenerative diseases (p < 0.008). Long-standing MS exhibits comparable global atrophy with lower WMV and thalamic volume when compared to other classical neurodegenerative diseases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Increasingly favorable mortality prognosis in multiple sclerosis (MS) raises questions regarding MS-specific cognitive aging and the presence of comorbidities such as Alzheimer's disease (AD)., Objective: To assess elderly with MS (EwMS) and age-matched healthy controls (HCs) using both MS- and AD-specific psychometrics., Methods: EwMS ( n = 104) and 56 HCs were assessed on a broad spectrum of language, visual-spatial processing, memory, processing speed, and executive function tests. Using logistic regression analysis, we examined cognitive performance differences between the EwMS and HC groups. Cognitive impairment (CI) was defined using a -1.5 SD threshold relative to age and education years-matched HCs, in two cognitive domains., Results: CI was observed in 47.1% of EwMS with differences most often seen on tests emphasizing cognitive processing speed as measured by Symbol Digit Modalities Test (SDMT) ( d = 0.9, p < 0.001) and verbal fluency (both category-based d = 0.87, p < 0.001; letter-based d = 0.67, p < 0.001). After adjusting for age, sex and years of education, MS/HC diagnosis was best predicted ( R 2 = 0.27) by differences in category-based verbal fluency (Wald = 9.935, p = 0.002) and SDMT (Wald = 13.937, p < 0.001)., Conclusion: This study confirms the common hallmark of slowed cognitive processing speed in MS among elderly patients. Defective verbal fluency, less often observed in younger cohorts, may represent emerging cognitive pathology due to other etiologies.

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 (Aβ 1-42 ) 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 Aβ 1-42 uptake suggesting a protective effect beyond physiological concentrations. Furthermore, in the presence of CHRFAM7A Aβ 1-42 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.

Adult-onset neuropsychiatric diseases are one of the most challenging areas of medicine. While symptomatic treatments are available, for most of these diseases the exact pathomechanism is not known, thus, disease-modifying therapies are difficult to conceptualize and find. The two most common and best studied neuropsychiatric diseases affecting higher cortical functions in humans are schizophrenia and Alzheimer's disease; both diseases have high heritability, however, the genetic architecture is not fully elucidated. Robust Single Nucleotide Variant (SNV) studies have identified several loci with modest effect sizes. While Copy Number Variants (CNV) make an important contribution to genetic variation, CNV GWAS suffer from dependence on mainly SNP arrays with underperforming genotyping accuracy. We evaluated dynamic range of the assays for three types of CNV loci, including biallelic deletion, high copy gain, and fusion gene, to assess the depth of exploration of the contribution of CNVs to disease susceptibility. Despite the suboptimal genotyping, novel mechanisms are emerging and further large-scale studies with genotyping assays optimized for CNV detection are needed. Furthermore, the CHRFAM7A human-specific fusion gene association warrants large scale locus specific association studies in AD, schizophrenia, bipolar disorder and ADHD.

Objectives: To explore whether the ability to recognize specific odorant items is differentially affected in aging versus Alzheimer disease (AD); to refine olfactory identification deficit (OID) as a biomarker of prodromal and early AD., Design: Prospective multicenter cross-sectional study with a longitudinal arm., Setting: Outpatient memory diagnostic clinics in New York and Texas., Participants: Adults aged 65 and older with amnestic mild cognitive impairment (aMCI) and AD and healthy aging (HA) subjects in the comparison group., Measurements: Participants completed the University of Pennsylvania Smell Identification Test (UPSIT) and neuropsychological testing. AD-associated odorants (AD-10) were selected based on a model of ordinal logistic regression. Age-associated odorants (Age-10) were identified using a linear model., Results: For the 841 participants (234 HA, 192 aMCI, 415 AD), AD-10 was superior to Age-10 in separating HA and AD. AD-10 was associated with a more widespread cognitive deficit across multiple domains, in contrast to Age-10. The disease- and age-associated odorants clustered separately in age and AD. AD-10 predicted conversion from aMCI to AD., Conclusions: Nonoverlapping UPSIT items were identified that were individually associated with age and disease. Despite a modest predictive value of the AD-specific items for conversion to AD, the AD-specific items may be useful in enriching samples to better identify those at risk for AD. Further studies are needed with monomolecular and unilateral stimulation and orthogonal biomarker validation to further refine disease- and age-associated signals., (Copyright © 2018 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

In vitro differentiation of human pluripotent stem cell into relevant cell types is a desirable model system that has the human biological context, is a renewable source, and is scalable. GABA interneurons and basal forebrain cholinergic neurons, derivates of the medial ganglionic eminence (MGE), are implicated in diverse neuropsychiatric diseases. Various protocols have been proposed to generate MGE progenitors: the embryoid body- (EB-) based rosette-derived (RD), the adherent (AdD), and the nonadherent (NAdD) approaches. While Wnt inhibition is frequently incorporated into the strategy, the timing varies between protocols and there is a lack of standardized outcome reporting, which precludes direct comparison. Here, we report a head-to-head comparison in three distinct experimental models to establish whether Wnt inhibition during neural stem cell, NSC (stage 1), or neural progenitor cell, NPC (stage 2), formation facilitates MGE differentiation. Wnt inhibition at both stages promotes MGE progenitor differentiation when compared to no inhibition. However, NSC (stage 1) Wnt inhibition markedly reduces the number of MGE progenitors available for downstream applications in the RD and the NAdD protocols due to early inhibition of proliferation. NPC (stage 2) Wnt inhibition in the adherent system is comparable to the EB-based methods offering a techically less challenging alternative.

Background: Cognitive impairment can be seen in patients of all ages with multiple sclerosis (MS). However, there is limited research on neurocognitive disorder in older adults with MS and how to detect Alzheimer's disease (AD) or its prodromal stage, amnestic mild cognitive impairment (aMCI). Thus, the MS clinician is challenged to discriminate between signs of MS-related cognitive decline versus a secondary neurodegenerative process., Objective: Compare cognition in older MS patients to patients with AD and aMCI., Methods: We evaluated cognitively impaired and unimpaired MS patients, AD patients, aMCI patients, and healthy controls (HCs), all elderly (n = 20 per group). AD and aMCI diagnoses were derived by consensus conference independent of the MS research project. Neuropsychological measures assessed domains commonly affected in AD, including verbal memory and expressive language., Results: Cognitively impaired and unimpaired MS groups did not differ on any measures sensitive to AD. Unimpaired MS patients were comparable to HCs. Impaired MS patients showed decreased semantic fluency, similar to aMCI patients. Lastly, while both AD and aMCI groups had deficient memory retention, there was no evidence of a retention deficit in either MS group., Conclusion: Our findings suggest that the cognitive profiles of MS and AD are distinct. In contrast to AD, MS is not associated with impairment of memory consolidation. However, there may be overlap between cognitive deficits related to MS and aMCI. Thus, evidence of poor memory retention, in an older MS patient may merit comprehensive dementia evaluation. The study is preliminary and includes no AD biomarkers (e.g., amyloid imaging) to confirm or rule out AD pathology., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: To determine if phenotypic personality traits modify the association of Apolipoprotein E (APOE) genotypes with different domains of cognitive function., Design: Cross-sectional., Methods: 172 non-demented older adults were administered the NEO-Five Factor Inventory (NEO-FFI), a battery of neuropsychological tests assessing memory, attention, executive function, language, and visuospatial ability, and underwent APOE genotyping. Multivariate (multiple-dependent variable) regression models predicting cognitive domains tested APOE interactions with personality traits, adjusting for age, sex, and education., Results: The APOE ε4 allele showed small to modest main effects on memory and executive function (1/3 SD deficits for carriers, p < .05), with ε2 status evidencing minimal and non-significant benefit. Neuroticism interacted with both ε2 and ε4 alleles in associations with attention scores (p = .001), with ε2 benefits and ε4 deficits being marked at high Neuroticism (Mean [M] covariate-adjusted Z-score = .39 for ε2, -.47 for ε4). The association of ε4 with memory was moderated by Conscientiousness (p < .001), such that ε4 memory deficits were apparent at low Conscientiousness (M = -.56), but absent at high levels of Conscientiousness. Weaker patterns (p < .05) also suggested ε4-related detriments in executive function only at lower Conscientiousness, and ε2 memory benefits only at higher Openness., Conclusions: Conscientiousness and Neuroticism moderate APOE associations with memory and executive function. As such, they may be useful phenotypic markers in refining the prognostic significance of this polymorphism. Effect-modifying personality traits also provide clues about behavioral and psychological factors that influence the cognitive impact of APOE. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Olfactory identification deficit (OID) has been associated with both aging and Alzheimer's disease (AD). In the context of an amnestic disorders, OID predicts conversion to AD. Neuroanatomical correlates could increase specificity and sensitivity and elucidate the mechanistic differences between OID in AD and aging. Cross-sectional analysis of white matter microstructural changes was performed using diffusion tensor imaging (DTI) and tract-based-spatial-statistics in amnestic mild cognitive impairment (aMCI), AD and normal controls (NC) in 66 subjects (26 AD, 15 aMCI, 25 NC). DTI 3-Tesla MRI scans were analyzed and subject level means for fractional anisotropy (FA), mean diffusivity (MD), radial and axial diffusivity (λ 1 D and λ 2,3 D) were calculated. Linear regression models were applied using DTI markers as predictor and OID as outcome. OID was associated with increased λ 1 D in aMCI and increased MD, λ 1 D and λ 2,3 D in AD. Voxel-wise analyses revealed widespread differences in all markers in AD. There were significant differences in λ 1 D in aMCI, particularly in the olfactory tract. OID is correlated with microstructural white matter changes as early as in aMCI. This study may help elucidate the biological basis for olfactory impairment in Alzheimer's disease. Neuroanatomical correlates could help distinguish OID associated with AD and that associated with aging., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: We evaluated smell identification as a biomarker for Alzheimer disease (AD) by assessing its utility in differentiating normal aging from an amnestic disorder and determining its predictive value for conversion from amnestic mild cognitive impairment (aMCI) to AD., Methods: Cross-sectional study (AD = 262, aMCI = 110, controls = 194) measuring smell identification (University of Pennsylvania Smell Identification Test [UPSIT]) and cognitive status was performed, as well as longitudinal analysis of aMCI participants (n = 96) with at least 1 year follow-up (mean 477.6 ± 223.3 days), to determine conversion by National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria., Results: Odor identification and disease status were highly correlated after correcting for age, sex, and APOE ( p < 0.001). Receiver operating characteristic (ROC)/area under the curve (AUC) was similar for the 40-item UPSIT, the top 10 smells in our study, and the 10-item subset previously proposed. Smeller/nonsmeller based on the 10-item subset with a cutoff of 7 (≤7, nonsmeller; >7, smeller) had a sensitivity and specificity of 88% and 71% for identifying AD and 74% sensitivity and 71% specificity for identifying an amnestic disorder. A total of 36.4% of participants with impaired olfaction and 17.3% with intact olfaction converted to AD ( p = 0.03). The ROC/AUC for prediction of conversion to AD was 0.62., Conclusions: Olfactory identification deficit is a useful screening tool for AD-related amnestic disorder, with sensitivity and specificity comparable to other established biomarkers, with benefits such as ease of administration and low cost. Olfactory identification deficit can be utilized to stratify risk of conversion from aMCI to AD and enrich clinical trials of disease-modifying therapy., Classification of Evidence: This study provides Class III evidence that smell identification (10-item UPSIT subset) accurately identifies patients with amnestic disorders.

Objective: Previous research shows that executive function (EF) and personality independently predict functional decline. Our objective was to determine whether personality traits predict independence with instrumental activities of daily living (IADLs), after accounting for executive dysfunction, in a mixed sample of patients with amnestic mild cognitive impairment (MCI) and Alzheimer disease (AD)., Methods: In a cross-sectional analysis at a university medical center, 63 healthy older adults (median age: 67.6 years; 71% women) and 119 patients (median age: 75.0 years; 58% women) with varying degrees of AD (probable AD: 85; possible AD: 3; amnestic MCI: 31) were studied. Standardized neuropsychological measures, NEO Five-Factor Inventory (NEO-FFI), and informant-report Lawton and Brody IADL scales were used. All participants underwent neuropsychological evaluation, including administration of self- and informant-report NEO-FFI. Patients additionally underwent neurologic examination, and their informants completed the Lawton and Brody IADL scale., Results: When testing the association between EF and personality on IADLs in the patient sample, conceptual card sorting, informant-report Openness, and informant-report Conscientiousness all significantly predicted IADLs, after accounting for age, education, and depression. In addition, a significant interaction showed that low Conscientiousness and executive dysfunction, in combination, can predict impairment of IADLs., Conclusion: Personality has a unique association with IADLs in patients with AD pathology that is not explained by EF. The findings confirm prior speculation that personality, in addition to cognitive dysfunction, is a risk factor for functional decline. Early identification of vulnerable individuals may allow for intervention to prolong functional independence., (Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Even in early stages, Alzheimer's disease (AD) is associated with olfactory deficit. We assess the association of volumetric differences in subcortical deep gray matter (DGM) structures and odor identification deficit (OID) in subjects with amnestic mild cognitive impairment (aMCI), AD and normal controls (NCs), and relate findings to the current gold standard right sided memory measure, visual reproduction. Eighty subjects (19 aMCI; 42 CE; 19 NC) were included in this study. We obtained olfactory testing and normalized structural brain volumes from 3T T1 MRI scans. Associations between MRI, olfactory- and memory impairment were studied using Pearson- and partial-correlation adjusted for age. AD patients had significantly higher olfactory deficits, lower visual reproduction scores, and reduced brain volumes (p<0.05). Within aMCI, OID was associated with lower right hippocampal- and left amygdala volume (p<0.05). In AD, OID was associated with bilaterally lower hippocampus and left amygdala volumes. In contrast, visual reproduction was associated with bilateral volume loss regardless of study group. OID is a more specific marker of early pathological right mesial-temporal involvement than the currently regarded gold standard of right sided-memory (visual reproduction). OID may be valuable in the longitudinal evaluation of disease modifying treatments in early disease course., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The complexity of human genetic variation has been extended by the observation of abundant and widespread variation in the copy number of submicroscopic DNA segments. The discovery of this novel level of genome organization opened new possibilities concerning the genetic variation that may confer susceptibility to or cause disease. Copy number variants (CNVs) influence gene expression, phenotypic variation and adaptation by altering gene dosage and genome organization. Concordant with the common disease common variant hypothesis these structural variants are now subject to interrogation for disease association. Alzheimer's disease (AD) is a progressive neurodegenerative disease with an estimated heritability of 60-80 %. Large scale genome-wide association studies (GWAS) using high frequency single nucleotide polymorphism (SNP) variants identified ten loci which do not account for the measured heritability. To find the missing heritability systematic assessment of all mutational mechanisms needs to be performed. Between the powerful SNP-GWAS studies and the planned Whole Genome Sequencing projects the contribution of copy number variation (CNV) to the genetic architecture of AD needs to be studied fully.

Background: Chondrosarcoma of the bladder is an extremely rare disease. Only five previously described cases are known in the medical literature., Patients and Methods: We present a chondrosarcoma developed 19 years after radiation treatment in a 73-year-old patient. A literature search of articles published from 1984 to 2014 was performed., Results: This is the first reported case of post-radiation bladder chondrosarcoma. We compared the clinicopathological features of the previously reported cases and reviewed the medical literature of the bladder sarcomas and post-radiation sarcomas., Conclusion: The primary treatment for bladder mesenchymal neoplasms is surgical, preferably radical cystectomy with or without chemotherapy. Positive surgical margin is one of the most important factors negatively affecting disease-specific, recurrence-free and overall survival rates., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Genetic heterogeneity is a common problem for genome-wide association studies of complex human diseases. Ordered-subset analysis (OSA) reduces genetic heterogeneity and optimizes the use of phenotypic information, thus improving power under some disease models. We hypothesized that in a genetically heterogeneous disorder such as Alzheimer's disease (AD), utilizing OSA by age at onset (AAO) of AD may increase the power to detect relevant loci. Using this approach, 8 loci were detected, including the chr15 : 30,44 region harboring CHRFAM7A. The association was replicated in the NIA-LOAD Familial Study dataset. CHRFAM7A is a dominant negative regulator of CHRNA7 function, the receptor that facilitates amyloid-β1-42 internalization through endocytosis and has been implicated in AD. OSA, using AAO as a quantitative trait, optimized power and detected replicable signals suggesting that AD is genetically heterogeneous between AAO subsets.

Background: We are developing the Neurological Disease Ontology (ND) to provide a framework to enable representation of aspects of neurological diseases that are relevant to their treatment and study. ND is a representational tool that addresses the need for unambiguous annotation, storage, and retrieval of data associated with the treatment and study of neurological diseases. ND is being developed in compliance with the Open Biomedical Ontology Foundry principles and builds upon the paradigm established by the Ontology for General Medical Science (OGMS) for the representation of entities in the domain of disease and medical practice. Initial applications of ND will include the annotation and analysis of large data sets and patient records for Alzheimer's disease, multiple sclerosis, and stroke., Description: ND is implemented in OWL 2 and currently has more than 450 terms that refer to and describe various aspects of neurological diseases. ND directly imports the development version of OGMS, which uses BFO 2. Term development in ND has primarily extended the OGMS terms 'disease', 'diagnosis', 'disease course', and 'disorder'. We have imported and utilize over 700 classes from related ontology efforts including the Foundational Model of Anatomy, Ontology for Biomedical Investigations, and Protein Ontology. ND terms are annotated with ontology metadata such as a label (term name), term editors, textual definition, definition source, curation status, and alternative terms (synonyms). Many terms have logical definitions in addition to these annotations. Current development has focused on the establishment of the upper-level structure of the ND hierarchy, as well as on the representation of Alzheimer's disease, multiple sclerosis, and stroke. The ontology is available as a version-controlled file at http://code.google.com/p/neurological-disease-ontology along with a discussion list and an issue tracker., Conclusion: ND seeks to provide a formal foundation for the representation of clinical and research data pertaining to neurological diseases. ND will enable its users to connect data in a robust way with related data that is annotated using other terminologies and ontologies in the biomedical domain.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with high prevalence, which imposes a substantial public health problem. The heritability of AD is estimated at 60-80% forecasting the potential use of genetic biomarkers for risk stratification in the future. Several large scale genome-wide association studies using high frequency variants identified 10 loci accountable for only a fraction of the estimated heritability. To find the missing heritability, systematic assessment of various mutational mechanisms needs to be performed. This copy number variation (CNV) genome-wide association study with age at onset (AAO) of AD identified 5 CNV regions that may contribute to the heritability of AAO of AD. Two CNV events are intragenic causing a deletion in CPNE4. In addition, to further study the mutational load at the 10 known susceptibility loci, CNVs overlapping with these loci were also catalogued. We identified rare small events overlapping CR1 and BIN1 in AD and normal controls with opposite CNV dosage. The CR1 events are consistent with previous reports. Larger scale studies with deeper genotyping specifically addressing CNV are needed to evaluate the significance of these findings.

Alzheimer disease (AD) is a devastating neurodegenerative disease affecting 1 in 68 in the population. An arbitrary cutoff 65 years as the age of onset to distinguish between early- and late-onset AD has been proposed and has been used in the literature for decades. As the majority of patients develop AD after 65 years of age, most clinical trials address this population. While the early-onset cases represent only 1% to 6% of AD cases, this population is the active working subset and thus contributes to a higher public health burden per individual, and early-onset cases are the most devastating at the level of the individual and their families. In this review, we compare and contrast the clinical, neuropsychological, imaging, genetic, biomarker, and pathological features of these two arbitrary groups. Finally, we discuss the ethical dilemma of non-abandonment and justice as it pertains to exclusion of the early-onset AD patients from clinical trials.

Background: Myelin protein zero (MPZ) is a critical structural component of myelin in the peripheral nervous system. The MPZ gene is regulated, in part, by the transcription factors SOX10 and EGR2. Mutations in MPZ, SOX10, and EGR2 have been implicated in demyelinating peripheral neuropathies, suggesting that components of this transcriptional network are candidates for harboring disease-causing mutations (or otherwise functional variants) that affect MPZ expression., Methodology: We utilized a combination of multi-species sequence comparisons, transcription factor-binding site predictions, targeted human DNA re-sequencing, and in vitro and in vivo enhancer assays to study human non-coding MPZ variants., Principal Findings: Our efforts revealed a variant within the first intron of MPZ that resides within a previously described SOX10 binding site is associated with decreased enhancer activity, and alters binding of nuclear proteins. Additionally, the genomic segment harboring this variant directs tissue-relevant reporter gene expression in zebrafish., Conclusions: This is the first reported MPZ variant within a cis-acting transcriptional regulatory element. While we were unable to implicate this variant in disease onset, our data suggests that similar non-coding sequences should be screened for mutations in patients with neurological disease. Furthermore, our multi-faceted approach for examining the functional significance of non-coding variants can be readily generalized to study other loci important for myelin structure and function.

Charcot-Marie-Tooth (CMT) disease comprises a genetically and clinically heterogeneous group of peripheral nerve disorders characterized by impaired distal motor and sensory function. Mutations in three genes encoding aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT disease primarily associated with an axonal pathology. ARSs are ubiquitously expressed, essential enzymes responsible for charging tRNA molecules with their cognate amino acids. To further explore the role of ARSs in CMT disease, we performed a large-scale mutation screen of the 37 human ARS genes in a cohort of 355 patients with a phenotype consistent with CMT. Here we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort. Functional analyses revealed that two of these mutations (p.Leu133His and p.Tyr173SerfsX7) severely affect enzyme activity. Interestingly, both functional variants were found in a single patient with CMT disease and additional neurological and non-neurological sequelae. Based on these data, KARS becomes the fourth ARS gene associated with CMT disease, indicating that this family of enzymes is specifically critical for axon function., (Copyright © 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders presenting with the phenotype of a chronic progressive neuropathy affecting both the motor and sensory nerves. During the last decade over two dozen genes have been identified in which mutations cause CMT. The disease illustrates a multitude of genetic principles, including diverse mutational mechanisms from point mutations to copy number variation (CNV), allelic heterogeneity, age-dependent penetrance and variable expressivity. Population based studies have determined the contributions of the various genes to disease burden enabling evidence-based approaches to genetic testing.

Mutations in the EGR2 gene cause a spectrum of Charcot-Marie-Tooth disease and related inherited peripheral neuropathies. We ascertained ten consecutive patients with various EGR2 mutations, report a novel de novo mutation, and provide longitudinal clinical data to characterize the natural history of the peripheral neuropathy. We confirmed that respiratory compromise and cranial nerve dysfunction are commonly associated with EGR2 mutations and can be useful in guiding molecular diagnosis. We also contrast morphological studies in the context of the I268N homozygous recessive mutation affecting the NAB repressor binding site and the R359W dominant-negative mutation in the zinc-finger domain.

Membrane-bound phosphoinositides are signalling molecules that have a key role in vesicle trafficking in eukaryotic cells. Proteins that bind specific phosphoinositides mediate interactions between membrane-bounded compartments whose identity is partially encoded by cytoplasmic phospholipid tags. Little is known about the localization and regulation of mammalian phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), a phospholipid present in small quantities that regulates membrane trafficking in the endosome-lysosome axis in yeast. Here we describe a multi-organ disorder with neuronal degeneration in the central nervous system, peripheral neuronopathy and diluted pigmentation in the 'pale tremor' mouse. Positional cloning identified insertion of ETn2beta (early transposon 2beta) into intron 18 of Fig4 (A530089I17Rik), the homologue of a yeast SAC (suppressor of actin) domain PtdIns(3,5)P2 5-phosphatase located in the vacuolar membrane. The abnormal concentration of PtdIns(3,5)P2 in cultured fibroblasts from pale tremor mice demonstrates the conserved biochemical function of mammalian Fig4. The cytoplasm of fibroblasts from pale tremor mice is filled with large vacuoles that are immunoreactive for LAMP-2 (lysosomal-associated membrane protein 2), consistent with dysfunction of the late endosome-lysosome axis. Neonatal neurodegeneration in sensory and autonomic ganglia is followed by loss of neurons from layers four and five of the cortex, deep cerebellar nuclei and other localized brain regions. The sciatic nerve exhibits reduced numbers of large-diameter myelinated axons, slowed nerve conduction velocity and reduced amplitude of compound muscle action potentials. We identified pathogenic mutations of human FIG4 (KIAA0274) on chromosome 6q21 in four unrelated patients with hereditary motor and sensory neuropathy. This novel form of autosomal recessive Charcot-Marie-Tooth disorder is designated CMT4J.

Mutations in mitofusin 2 (MFN2) have been reported in Charcot-Marie-Tooth type 2 (CMT2) families. To study the distribution of mutations in MFN2 we screened 323 families and isolated patients with distinct CMT phenotypes. In 29 probands, we identified 22 distinct MFN2 mutations, and 14 of these mutations have not been reported before. All mutations were located in the cytoplasmic domains of the MFN2 protein. Patients presented with a classical but rather severe CMT phenotype, since 28% of them were wheelchair-dependent. Some had additional features as optic atrophy. Most patients had an early onset and severe disease status, whereas a smaller group experienced a later onset and milder disease course. Electrophysiological data showed in the majority of patients normal to slightly reduced nerve conduction velocities with often severely reduced amplitudes of the compound motor and sensory nerve action potentials. Examination of sural nerve specimens showed loss of large myelinated fibres and degenerative mitochondrial changes. In patients with a documented family history of CMT2 the frequency of MFN2 mutations was 33% indicating that MFN2 mutations are a major cause in this population.

Purpose: An evidence-based approach was used to determine the frequency distribution of genes contributing to the Charcot-Marie-Tooth (CMT) disease phenotype., Methods: We performed a combined analysis of 11 population-based studies from various ethnic backgrounds to generate an evidence-based testing scheme. To estimate the relative frequencies of the responsible genes for which population-based studies are not available, we used our cohort of clinically classified patients with CMT and related neuropathies collected before the availability of genetic testing., Results: Similar mutation frequencies were detected in the various studies, revealing a uniform distribution of pathogenic mutations. In CMT1 70% of patients harbor the CMT1A duplication, followed by GJB1 mutations at 8.8%. MPZ and PMP22 mutations are less common, identified on average in 2.9% and 1.5% of patients, respectively. Other genes not tested in population-based studies contribute to less than 1% of disease individually. In CMT2 MFN2 mutations are the most common, although population-based studies are not yet available., Conclusion: CMT represents a heterogeneous group of disorders at the molecular level. Nevertheless, testing for the CMT1A duplication (i.e., duplication of PMP22) alone yields an accurate molecular diagnosis in approximately half of all patients. If one further specifies the clinical type (demyelinating vs. axonal), the yield of detecting a molecular defect increases to 75% to 80% in the demyelinating or CMT1 group with a screening test that evaluates for CMT1A duplication/hereditary neuropathy with liability to pressure palsies deletion and GJB1 point mutations.

Objective: To determine the clinical consequences of the PMP22 point mutation, T118M, which has been previously considered to either cause an autosomal recessive form of Charcot-Marie-Tooth (CMT) disease or be a benign polymorphism., Methods: We analyzed patients from five separate kindreds and characterized their peripheral nerve function by clinical and electrophysiological methods., Results: All heterozygous patients had clinical and/or electrophysiological features of a neuropathy similar to hereditary neuropathy with liability to pressure palsies (HNPPs). The homozygous patient had a severe axonal neuropathy without features of demyelination., Interpretation: These findings suggest that T118M PMP22 retains some normal PMP22 activity, allowing the formation of compact myelin and normal nerve conduction velocities in the homozygous state. Taken together, these findings suggest that T118M is a pathogenic mutation causing a dominantly inherited form of CMT by a partial loss of PMP22 function.

DNA diagnostics plays an important role in the characterization and management of patients manifesting inherited peripheral neuropathies. We describe the clinical integration of molecular diagnostics with medical history, physical examination, and electrophysiological studies. Molecular testing can help establish a secure diagnosis, enable genetic counseling regarding recurrence risk, potentially provide prognostic information, and in the near future may be important for the choice of therapies.

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral neuropathies characterized by progressive weakness and atrophy of distal limb muscles. Recently, SIMPLE/LITAF was shown to be responsible for an autosomal dominant demyelinating form of CMT linked to 16p (CMT1C). Although two transcripts encoding different proteins (SIMPLE and LITAF) have been reported from the same gene, we could not confirm the existence of LITAF. Here we show that the LITAF transcript appears to result from a DNA sequencing error. We screened the SIMPLE gene for mutations in a cohort of 192 patients with CMT or related neuropathies, each of whom tested negative for other known genetic causes of CMT. In 16 unrelated CMT families we identified nine different nucleotide variations in SIMPLE that were not detected in control chromosomes. SIMPLE mutations can occur de novo, associated with sporadic CMT1 and may convey both demyelinating and axonal forms. Bioinformatics analyses and other observations of SIMPLE suggest that 1) it could be a member of the RING finger motif-containing subfamily of E3 ubiquitin ligases that are associated with the ubiquitin-mediated proteasome processing pathway, 2) it could interact through its PPXY motifs with a WW domain containing protein, for instance with NEDD4, an E3 ubiquitin ligase, and 3) it could interact through the PSAP motif with TSG10, a protein associated with endosomal multivesicular protein sorting. Since both SIMPLE and Hrs are endosomal proteins and have both PPXY and P(S/T)AP motifs, we hypothesize that SIMPLE, like Hrs, is potentially a clathrin adaptor aiding in the retention of ubiquitinated proteins on to the endosomes. Thus the potential E3 ubiquitin ligase activity of SIMPLE, alteration in its interactions with NEDD4 or TSG101, or changes in its properties as a clathrin coat adaptor may underlie the pathogenesis of Charcot-Marie-Tooth disease.

During the last decade, 18 genes and 11 additional loci harboring candidate genes have been associated with Charcot-Marie-Tooth disease (CMT) and related peripheral neuropathies. Ten of these 18 genes have been identified in the last 2 years. This phenomenal pace of CMT gene discovery has fomented an unprecedented explosion of information regarding peripheral nerve biology and its pathologic manifestations in CMT. This review integrates molecular genetics with the clinical phenotypes and provides a flowchart for molecular-based diagnostics. In addition, we discuss rational approaches to molecular therapeutics, including novel biologic molecules (eg, small interfering ribonucleic acid [siRNA], antisense RNA, and ribozymes) that potentially could be used as drugs in the future. These may be applicable in attempts to normalize gene expression in cases of CMT type 1A, wherein a 1.5 Mb genomic duplication causes an increase in gene dosage that is associated with the majority of CMT cases. Aggresome formation by the PMP22 gene product, the disease-associated gene in the duplication cases, could thus be avoided. We also discuss alternative therapeutics, in light of other neurodegenerative disorders, to disrupt such aggresomes. Finally, we review rational therapeutic approaches, including the use of antioxidants such as vitamin E, coenzyme Q10, or lipoic acid to relax potential oxidative stress in peripheral nerves, for CMT management.

We report a case of congenital hypomyelination associated with cranial nerve dysfunction, respiratory failure, and hypertrophic cardiomyopathy confounding the clinical picture. Molecular genetic testing showed a complex de novo myelin protein zero (MPZ) mutation consisting of a 3bp deletion of CTA from nucleotide 550 to 552 and insertion of G at nucleotide 550 that by conceptual translation results in a frameshift mutation. Muscle biopsy findings are presented that allude to the effect of abnormal innervation on early postnatal muscle differentiation.