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Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper respiratory tract complication where the pathogenesis is largely unknown. Herein, we investigated the transcriptome profile in nasal mucosa biopsies of CRSwNP patients and healthy individuals. We further integrated the transcriptomics data with genes located in chromosomal regions containing genome-wide significant gene variants for COVID-19. Among the most significantly upregulated genes in polyp mucosa were CCL18, CLEC4G, CCL13 and SLC9A3. Pathways involving "Ciliated epithelial cells" were the most differentially expressed molecular pathways when polyp mucosa and non-polyp mucosa from the same patient was compared. Natural killer T-cell (NKT) and viral pathways were the most statistically significant pathways in the mucosa of CRSwNP patients compared with those of healthy control individuals. Upregulated genes in polyp mucosa, located within the genome-wide associated regions of COVID-19, included LZTFL1, CCR9, SLC6A20, IFNAR1, IFNAR2 and IL10RB. Interestingly, the second most over-expressed gene in our study, CLEC4G, has been shown to bind directly to SARS-CoV-2 spike's N-terminal domain and mediate its entry and infection. Our results on altered expression of genes related to cilia and viruses point to the de-regulation of viral defenses in CRSwNP patients, and may give clues to future intervention strategies., (© 2023. The Author(s).)

Mitochondrial morphology, distribution and function are maintained by the opposing forces of mitochondrial fission and fusion, the perturbation of which gives rise to several neurodegenerative disorders. The large guanosine triphosphate (GTP)ase dynamin-related protein 1 (Drp1) is a critical regulator of mitochondrial fission by mediating membrane scission, often at points of mitochondrial constriction at endoplasmic reticulum (ER)-mitochondrial contacts. Hereditary spastic paraplegia (HSP) subtype SPG61 is a rare neurodegenerative disorder caused by mutations in the ER-shaping protein Arl6IP1. We have previously reported defects in both the ER and mitochondrial networks in a Drosophila model of SPG61. In this study, we report that knockdown of Arl6IP1 lowers Drp1 protein levels, resulting in reduced ER-mitochondrial contacts and impaired mitochondrial load at the distal ends of long motor neurons. Increasing mitochondrial fission, by overexpression of wild-type Drp1 but not a dominant negative Drp1, increases ER-mitochondrial contacts, restores mitochondrial load within axons and partially rescues locomotor deficits. Arl6IP1 knockdown Drosophila also demonstrate impaired autophagic flux and an accumulation of ubiquitinated proteins, which occur independent of Drp1-mediated mitochondrial fission defects. Together, these findings provide evidence that impaired mitochondrial fission contributes to neurodegeneration in this in vivo model of HSP.

The hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative conditions whose characteristic feature is degeneration of the longest axons within the corticospinal tract which leads to progressive spasticity and weakness of the lower limbs. Though highly genetically heterogeneous, the majority of HSP cases are caused by mutations in genes encoding proteins that are responsible for generating and organizing the tubular endoplasmic reticulum (ER). Despite this, the role of the ER within neurons, particularly the long axons affected in HSP, is not well understood. Throughout axons, ER tubules make extensive contacts with other organelles, the cytoskeleton and the plasma membrane. At these ER contacts, protein complexes work in concert to perform specialized functions including organelle shaping, calcium homeostasis and lipid biogenesis, all of which are vital for neuronal survival and may be disrupted by HSP-causing mutations. In this article we summarize the proteins which mediate ER contacts, review the functions these contacts are known to carry out within neurons, and discuss the potential contribution of disruption of ER contacts to axonopathy in HSP., (Copyright © 2019 Fowler, Garcia-Pardo, Simpson and O’Sullivan.)

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterized by degeneration of the longest motor neurons in the corticospinal tract, leading to muscle weakness and spasticity of the lower limbs. Pathogenic variants in genes encoding proteins that shape the endoplasmic-reticulum (ER) network are a leading cause of HSP, however, the mechanisms by which loss of ER-shaping proteins underpin degeneration of selective neurons in HSP remain poorly understood. To begin to address this, we have generated a novel in vivo model of HSP in Drosophila melanogaster by targeted knockdown of the ER-shaping protein Arl6IP1 Variants in the human homolog of this gene have recently been linked to HSP subtype SPG61. Arl6IP1 RNAi flies display progressive locomotor deficits without a marked reduction in lifespan, recapitulating key features of HSP in human patients. Loss of Arl6IP1 leads to fragmentation of the smooth ER and disrupted mitochondrial network organization within the distal ends of long motor neurons. Furthermore, genetically increasing mitochondrial fission, by overexpression of dynamin-related protein 1 (Drp1), restores mitochondrial network organization and rescues locomotor deficits in two independent Drosophila models of HSP. Taken together, these results propose a role for ER-shaping proteins in mitochondrial network organization in vivo and suggest that impaired mitochondrial organization may be a common mechanism underpinning some forms of HSP., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative conditions characterised by retrograde degeneration of the longest motor neurons in the corticospinal tract, resulting in muscle weakness and spasticity of the lower limbs. To date more than 70 genetic loci have been associated with HSP, however the majority of cases are caused by mutations that encode proteins responsible for generating and maintaining tubular endoplasmic reticulum (ER) structure. These ER-shaping proteins are vital for the long-term survival of axons, however the mechanisms by which mutations in these proteins give rise to HSP remain poorly understood. To begin to address this we have characterized in vivo loss of function models of two very rare forms of HSP caused by loss of the ER-shaping proteins ARL6IP1 (SPG61) and RTN2 (SPG12). These models display progressive locomotor defects, disrupted organisation of the tubular ER and length-dependant defects in the axonal mitochondrial network. Here we compare our findings with those associated with more common forms HSP including: Spastin, Atlastin-1 and REEP 1 which together account for over half of all cases of autosomal dominant HSP. Furthermore, we discuss recent observations in other HSP models which are directly implicated in mitochondrial function and localization. Overall, we highlight the common features of our rare models of HSP and other models of disease which could indicate shared mechanisms underpinning neurodegeneration in these disorders.

The present example illustrates a method for assessing pattern similarity for correlation matrices from populations known to differ in clinically important respects. The data underlying previously published confirmatory factor analyses of neuropsychological traits are presented in two methods for assessing whether the matrices are similar enough to justify their aggregation into a single composite matrix. The significance of this procedure for research in applied neuropsychology is commented upon in terms of the benefits to model diagnostics.

Trait analyses of the Luria-Nebraska's Intellectual Processes, Motor Functions, and Memory Scales were performed using multitrait-multimethod procedures and confirmatory factor analysis. Three measures each of intellectual, motor, and memory functions were administered to 161 neuropsychiatric patients. Intellectual scales (viz., Luria-Nebraska and WAIS-R) were found to have convincing discriminant properties, but motor and memory measures demonstrated visibly less such robustness. Confirmatory factor analyses supported a three-factor model of the 9 x 9 matrix, in which each of the three Luria-Nebraska scales serves as a marker for the factors. Issues related to the neuropsychological constructs, test construction, and construct validity of measurement procedures employed in clinical neuropsychology are discussed.

An exploratory maximum likelihood factor analysis of the inter-correlations among the 11 subtests of the WAIS-R was undertaken for 167 patients who had a primary diagnoses of cerebrovascular accident (right hemisphere, n = 79; left hemisphere, n = 55; diffuse or multifocal, n = 33). On the WAIS-R, this sample performed below normative standards (average scaled score = 7.1), but demonstrated a pattern of variability among subtests similar to the normative groups. Interestingly, VIQ-PIQ discrepancy analyses revealed V > P profiles for patients with lesions in either or both hemispheres. The best fit for the WAIS-R matrix was an oblique two-factor model comprised of the Verbal and Performance subtests. This factor solution, which was moderately correlated (.52), accounted for 58.8% of the total variance. The stability of a two-factor structure in this neurologic impaired population suggests that the WAIS-R is a robust measure, even when used within such a rehabilitation population. Only two of the eleven subtests (i.e., Comprehension and Picture Arrangement), however, were related to lesion site. Rehabilitation settings may need to rely more on neuropsychological procedures that measure the more "fluid" areas of neurocognitive ability, in contrast to the WAIS-R which appears less sensitive to the neurological impairment associated with stroke.

One hundred seventy-nine psychiatric inpatients were administered the WAIS-R and several neuropsychological and academic achievement tests. All subjects were assigned to three groups based on their WAIS-R's VIQ-PIQ discrepancy scores: (i) Low Verbal (Verbal IQ < Performance IQ. by at least 13 points); (ii) Low Performance (Performance IQ < Verbal IQ by at least 13 points); and (iii) Equal (Verbal IQ-Performance IQ within 13 points). The Low Verbal group made significantly more errors on the Speech Sounds Perception Test, demonstrated lower spelling scores, evinced more aphasic signs, and had had more special education placements than did the Equal or Low Performance groups. The Low Performance subjects demonstrated significantly more signs of constructional dyspraxia and performed more poorly on the Grooved Pegboard test. The neuropsychiatric patients who had Verbal-Performance IQ discrepancies of at least one standard deviation may be at risk for specific, subtle neuropsychological deficits.

Five multifactor models, in both orthogonal and oblique versions, and a single-factor model of the WAIS-R's factor pattern were examined by confirmatory maximum likelihood factor analyses of a data matrix constructed from the results for 90 neuropsychiatric patients. None of the models fits the data matrix in an absolute sense, even though all of the models represented an improvement over a null statistical model. For the multifactor models, the best results were obtained by oblique solutions, in which the degree of correlation between the factors varied from .71 to .93. The single-factor model fit nearly as well as, and in some instances better than, many of the multifactor models. The best-fitting model, viz., a three-factor oblique one, was only marginally better in its fit than two of the three two-factor models or the competing three-factor model.

The Mini-Mental State Examination (MMSE) and the Blessed Orientation-Memory-Concentration test (BOMC) were each administered to 110 nursing home residents. The correlation between the MMSE and BOMC's total score was -.79. Maximum likelihood factor analysis revealed a two-factor structure, consisting of memory-attention and verbal-comprehension factors that were highly correlated (.69). The results suggest that the somewhat longer MMSE may be preferred for bedside mental status testing, as it clearly measures an additional dimension of cognitive ability, while the BOMC is primarily a unidimensional test. The theoretical and clinical implications of bedside mental status testing of elderly patients are discussed.

Presented for 64 Ss a replication of the Family Environment Scale's maximum likelihood factor structure for which the two-factor, Varimax-rotated solution was found to be stable when the correlations among the subscales were corrected for the effects of social desirability response bias. As reported previously (Fowler, 1981), the first bipolar dimension, "cohesion vs. conflict," measures relationship-centered concerns, while the second bipolar axis "organization-control," reflects basic system-maintenance properties of family activity. These two factors are comparable to others reported in small-group research, parent-child interaction studies, and human communication investigations. A comprehensive statistical model of the Family Environment Scale can be constructed where the semantic space of the 10 subscales reflects the two supraordinate concepts of "interpersonal cohesion" and "control." It is not yet known to what extent the modeling of this impression-space can be expanded to reveal dependencies on imminent (familial and individual) cognitive and personality schemata.

One hundred eight epileptic patients (59 men, 49 women; 55% partial seizures, 45% generalized) were examined on 45 indices comprising a modified Halstead Neuropsychological Test Battery. Factor analyses identified five dimensions: Verbal Comprehension, Perceptual Organization, Selective Attention, Motor Skills, Abstract Reasoning. These factors are similar to those previously reported for neurocognitive abilities in several different populations. Relative deficits on Verbal Comprehension and Abstract Reasoning were related, as predicted, to left hemispheric dysfunction as indexed by EEG localization. Perceptual Organization demonstrated a further, predictable relationship to right hemispheric function. Deficits on Selective Attention were not clearly lateralized, being correlated with a wide variety of electroencephalographic abnormalities. The implications of these findings for the use of neurocognitive profiles in treatment planning for this population are discussed.

The current study examines the factor pattern of the Wechsler Adult Intelligence Scale for a sample of 151 neuropsychiatric inpatients (97 men, 54 women). As expected, these patients performed less well on all 11 of the subtests and ranged from .60 to 1.54 SD below normative standards. These patients were neither more variable nor were the intercorrelations among the subtests lower than those of the normative group. As in previous research, maximum likelihood factor analyses revealed the presence of a Verbal Comprehension dimension and a Perceptual Organization dimension, factors that were moderately correlated (.60). The stability of a two-factor solution for the WAIS in this population and its implications for the inclusion of the WAIS as a component of a neuropsychological assessment paradigm are discussed.

The current study examines the sensitivity of the Wechsler Adult Intelligence Scale in predicting performance on a modified Halstead Neuropsychological Test Battery for lower-functioning neuropsychiatric inpatients (97 men, 54 women). Regression analyses support earlier-reported findings that the WAIS's subtests more accurately predict neuropsychological test performance than do the WAIS IQ's alone. The IQ's and scaled scores respectively predicted 27% and 39% of the variance in the Halstead's measures. The overall relationship between neurocognitive and WAIS indices is somewhat greater than previous reports and is apparently due to the fact that the lower the overall level of cognitive ability, the lower is neuropsychological functioning in general. However, since most of the variance in the modified Halstead Battery was not common with the WAIS's indices, these findings continue to support the practice of including both sets of measures as part of a comprehensive neuropsychological assessment paradigm for such patients. The importance of developing instruments and procedures which more precisely measure "fluid" neurocognitive abilities is underscored.

An oblique, five-factor model of a modified Halstead-Reitan Neuropsychological Test Battery is presented. One hundred fifty-one neuropsychiatric inpatients (94 men, 57 women) were examined on 44 neuropsychological indices. Five correlated dimensions (r = .25), viz., Verbal Comprehension, Perceptual Organization, Sensory-attention, Primary Motor, and Tactile-spatial abilities, were identified by maximum likelihood factor analyses of this correlation matrix. These findings are quite similar to those reported earlier by Fowler, Richards, Berent, and Boll (1985, 1987) and Royce, Yeudall, and Bock (1976). The factors may be broadly categorized using the distinction made by Lezak (1983) for verbal, nonverbal, and mental activity variables. MANOVAs revealed systematic relationships between simple-weighted factor scores and: (1) the overall level of cognitive functioning (p less than .01), as well as (2) psychiatric diagnosis (p less than .01). Implications of these findings for understanding the impact of neuropsychiatric disorders on the structure of abilities for such patients are developed.

The pattern and level of performance on the WAIS-R and the Luria-Nebraska's Intelligence, Memory, and Motor Scales were examined for 93 neurologically impaired adults. Maximum likelihood factor analyses of the WAIS-R indicated the presence of strongly correlated (.72) Verbal Comprehension and Perceptual Organization dimensions. Comparisons of these factors to those of the standardization group revealed an acceptable level of similarity (.94) for Verbal Comprehension, but not for Perceptual Organization (.53). Canonical correlations between WAIS-R factor scores and the three Luria-Nebraska scaled scores accounted for 82% of the total variance. Each set of procedures evidently is indexing the same theoretical constructs. Implications of these findings for our understanding of the measurement models that underlie clinical neuropsychology are discussed.