FXTAS Neuropathology Includes Widespread Reactive Astrogliosis and White Matter Specific Astrocyte Degeneration.

OBJECTIVE: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset progressive genetic neurodegenerative disorder that occurs in FMR1 premutation carriers. The temporal, spatial, and cell-type specific patterns of neurodegeneration in the FXTAS brain remain incompletely characterized. Intranuclear inclusion bodies are the neuropathological hallmark of FXTAS, which are largest and occur most frequently in astrocytes, glial cells that maintain brain homeostasis. Here, we characterized neuropathological alterations in astrocytes in multiple regions of the FXTAS brain. METHODS: Striatal and cerebellar sections from FXTAS cases (n = 12) and controls (n = 12) were stained for the astrocyte markers glial fibrillary acidic protein (GFAP) and aldehyde dehydrogenase 1L1 (ALDH1L1) using immunohistochemistry. Reactive astrogliosis severity, the prevalence of GFAP+ fragments, and astrocyte density were scored. Double label immunofluorescence was utilized to detect co-localization of GFAP and cleaved caspase-3. RESULTS: FXTAS cases showed widespread reactive gliosis in both grey and white matter. GFAP staining also revealed remarkably severe astrocyte pathology in FXTAS white matter - characterized by a significant and visible reduction in astrocyte density (-38.7% in striatum and - 32.2% in cerebellum) and the widespread presence of GFAP+ fragments reminiscent of apoptotic bodies. White matter specific reductions in astrocyte density were confirmed with ALDH1L1 staining. GFAP+ astrocytes and fragments in white matter were positive for cleaved caspase-3, suggesting that apoptosis-mediated degeneration is responsible for reduced astrocyte counts. INTERPRETATION: We have established that FXTAS neuropathology includes robust degeneration of astrocytes, which is specific to white matter. Because astrocytes are essential for maintaining homeostasis within the central nervous system, a loss of astrocytes likely further exacerbates neuropathological progression of other cell types in the FXTAS brain. ANN NEUROL 2024;95:558-575.

Brain Metabolomics in Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).

The course of pathophysiological mechanisms involved in fragile X-associated tremor/ataxia syndrome (FXTAS) remains largely unknown. Previous proteomics and metabolomics studies conducted in blood samples collected from FMR1 premutation carriers with FXTAS reported abnormalities in energy metabolism, and precursors of gluconeogenesis showed significant changes in plasma expression levels in FMR1 premutation carriers who developed FXTAS. We conducted an analysis of postmortem human brain tissues from 44 donors, 25 brains with FXTAS, and 19 matched controls. We quantified the metabolite relative abundance in the inferior temporal gyrus and the cerebellum using untargeted mass spectrometry (MS)-based metabolomics. We investigated how the metabolite type and abundance relate to the number of cytosine-guanine-guanine (CGG) repeats, to markers of neurodegeneration, and to the symptoms of FXTAS. A metabolomic analysis identified 191 primary metabolites, the data were log-transformed and normalized prior to the analysis, and the relative abundance was compared between the groups. The changes in the relative abundance of a set of metabolites were region-specific with some overlapping results; 22 metabolites showed alterations in the inferior temporal gyrus, while 21 showed differences in the cerebellum. The relative abundance of cytidine was decreased in the inferior temporal gyrus, and a lower abundance was found in the cases with larger CGG expansions; oleamide was significantly decreased in the cerebellum. The abundance of 11 metabolites was influenced by changes in the CGG repeat number. A histological evaluation found an association between the presence of microhemorrhages in the inferior temporal gyrus and a lower abundance of 2,5-dihydroxypyrazine. Our study identified alterations in the metabolites involved in the oxidative-stress response and bioenergetics in the brains of individuals with FXTAS. Significant changes in the abundance of cytidine and oleamide suggest their potential as biomarkers and therapeutic targets for FXTAS.

Synaptic boutons are smaller in chandelier cell cartridges in autism.

Chandelier (Ch) cells are cortical interneurons with axon terminal structures known as cartridges that synapse on the axon initial segment of excitatory pyramidal neurons. Previous studies indicate that the number of Ch cells is decreased in autism, and that GABA receptors are decreased in the Ch cell synaptic target in the prefrontal cortex. To further identify Ch cell alterations, we examined whether the length of cartridges, and the number, density, and size of Ch cell synaptic boutons, differed in the prefrontal cortex of cases with autism versus control cases. We collected samples of postmortem human prefrontal cortex (Brodmann Area (BA) 9, 46, and 47) from 20 cases with autism and 20 age- and sex-matched control cases. Ch cells were labeled using an antibody against parvalbumin, a marker that labeles soma, cartridges, and synaptic boutons. We found no significant difference in the average length of cartridges, or in the total number or density of boutons in control subjects vs. subjects with autism. However, we found a significant decrease in the size of Ch cell boutons in those with autism. The reduced size of Ch cell boutons may result in reduced inhibitory signal transmission and impact the balance of excitation to inhibition in the prefrontal cortex in autism.

Distinct patterns of GABAergic interneuron pathology in autism are associated with intellectual impairment and stereotypic behaviors.

LAY ABSTRACT: Autism spectrum disorder is a neurodevelopmental condition characterized by deficits in sociability and communication and the presence of repetitive behaviors. How specific pathological alterations of the brain contribute to the clinical profile of autism spectrum disorder remains unknown. We previously found that a specific type of inhibitory interneuron is reduced in number in the autism spectrum disorder prefrontal cortex. Here, we assessed the relationship between interneuron reduction and autism spectrum disorder symptom severity. We collected clinical records from autism spectrum disorder (n = 20) and assessed the relationship between the severity of symptoms and interneuron number. We found that the reduced number of inhibitory interneurons that we previously reported is linked to specific symptoms of autism spectrum disorder, particularly stereotypic movements and intellectual impairments.

Undersizing mitral annuloplasty alters left ventricular mechanics in a swine model of ischemic mitral regurgitation.

OBJECTIVE: Undersizing mitral annuloplasty (UMA) is a frequently used surgical repair technique to correct ischemic mitral regurgitation in patients with heart failure. In this study, we sought to test the hypothesis that downsizing the mitral annulus can adversely affect the shape and mechanics of the left ventricle inhibiting its functional recovery. METHODS: Eighteen farm swine that underwent an inferolateral myocardial infarction and developed ischemic mitral regurgitation of >2+ severity after 2 months were assigned as follows: 9 swine received an undersized mitral annuloplasty, 6 received papillary muscle approximation (PMA), and 3 animals did not receive any other intervention. Animals lived another 3 months and cardiac magnetic resonance imaging was performed before termination to assess ventricle mechanics and function. RESULTS: Ejection fraction was comparable between the 2 repair groups before surgery, but was significantly lower in UMA at 38.89% ± 7.91% versus 50.83% ± 9.04% in the PMA group (P = .0397). Animals receiving UMA had lower regional peak fractional shortening and reduced systolic and diastolic radial velocities compared with PMA and in some regions were lower than sham. Animals that underwent UMA had higher circumferential strain than sham, but lower than PMA. UMA animals have lower longitudinal strain compared to sham group and lower LV torsion than PMA. CONCLUSIONS: Undersizing the mitral annulus with an annuloplasty ring can restore valvular competence, but unphysiologically impair ventricle mechanics. Mitral valve repair strategies should focus not only on restoring valve competence, but preserving ventricle mechanics.

Redefining varicose projection astrocytes in primates.

Varicose projection astrocytes (VP-As) are found in the cerebral cortex and have been described to be specific to humans and chimpanzees. To further examine the phylogenetic distribution of this cell type, we analyzed cortical tissue from several primates ranging from primitive primates to primates evolutionary closer to human such as apes. We specifically analyzed tissue from four strepsirrhine species, one tarsier, six species of platyrrhine monkeys, ten species of cercopithecoid monkeys, two hylobatid ape species, four to six cases each of chimpanzee, bonobo, gorilla, and orangutan, and thirteen human. We found that VP-As were present only in human and other apes (hominoids) and were absent in all other species. We showed that VP-As are localized to layer VI and the superficial white matter of the cortex. The presence of VP-As co-occured with interlaminar astrocytes that also had varicosities in their processes. Due to their location, their long tangential processes, and their irregular presence within species, we propose that VP-As are astrocytes that develop varicosities under specific conditions and that are not a distinct astrocyte type.

Risk factors associated with sacral stress fractures: a systematic review.

OBJECTIVES: The objective of this study was to examine and identify risk factors associated with the development of sacral stress fractures in order to improve diagnosis in clinical practice. METHODS: Electronic search strategies in PubMed, CINAHL, Scopus, and SPORTDiscus were combined with a hand search to identify articles for inclusion. Studies were considered if they described patient cases in which imaging confirmed diagnosis of a sacral stress fracture, and the diagnosis included whether the fracture was a sacral insufficiency or sacral fatigue stress fracture. RESULTS: In those that developed sacral insufficiency fractures, the risk factors that were most prevalent included osteoporosis, pelvic radiation therapy, rheumatoid arthritis, long-term corticosteroid therapy, and postmenopausal, each with a prevalence of 100%. Risk factors with 100% prevalence in those diagnosed with sacral fatigue fractures included recent increase in training intensity and deficient diet. DISCUSSION: A pattern of signs and symptoms are consistent among subjects with sacral stress fractures. Patients being unsuccessfully treated for low-back and buttock pain who fit the risk factor profiles for sacral stress fractures should be referred to a physician for further diagnostic workup.